Sandbox Reserved 1491 - Revision history

Emeric Goetz at 10:37, 11 January 2019

Emeric Goetz — Fri, 11 Jan 2019 10:37:30 GMT

←Older revision		Revision as of 10:37, 11 January 2019
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	==2xml - KDM4C catalytic domain==		==2xml - KDM4C catalytic domain==

-	'''2xml''' is a 2 chain structure. This domain belongs to the [https://en.wikipedia.org/wiki/Human Human] ~~'''~~KDM4C~~'''~~ protein.	+	'''2xml''' is a 2 chain structure. This domain belongs to the [https://en.wikipedia.org/wiki/Human Human] KDM4C protein.

	[https://en.wikipedia.org/wiki/KDM4C KDM4C] is a '''histone demethylase''' involved in the specific demethylation of trimethylated residues (Lys 9 and Lys 36 of histone 3).		[https://en.wikipedia.org/wiki/KDM4C KDM4C] is a '''histone demethylase''' involved in the specific demethylation of trimethylated residues (Lys 9 and Lys 36 of histone 3).
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	'''Genes expression''' is directly related to the '''condensation state''' of the [https://en.wikipedia.org/wiki/Chromatin chromatin]. Indeed, chromatin can be in the form of [https://en.wikipedia.org/wiki/Heterochromatin heterochromatin] (condensed form of DNA) or [https://en.wikipedia.org/wiki/Euchromatin euchromatin] (relaxed form of DNA) which correspond respectively to the transcriptionally silent and active forms of DNA. Chromatin is composed of DNA wrapped around [https://en.wikipedia.org/wiki/Histone histone] octamers forming nucleosomes<ref>Tamaru, H. “Confining Euchromatin/Heterochromatin Territory: Jumonji Crosses the Line.” Genes & Development 24, no. 14 (July 15, 2010): 1465–78. https://doi.org/10.1101/gad.1941010.</ref>.		'''Genes expression''' is directly related to the '''condensation state''' of the [https://en.wikipedia.org/wiki/Chromatin chromatin]. Indeed, chromatin can be in the form of [https://en.wikipedia.org/wiki/Heterochromatin heterochromatin] (condensed form of DNA) or [https://en.wikipedia.org/wiki/Euchromatin euchromatin] (relaxed form of DNA) which correspond respectively to the transcriptionally silent and active forms of DNA. Chromatin is composed of DNA wrapped around [https://en.wikipedia.org/wiki/Histone histone] octamers forming nucleosomes<ref>Tamaru, H. “Confining Euchromatin/Heterochromatin Territory: Jumonji Crosses the Line.” Genes & Development 24, no. 14 (July 15, 2010): 1465–78. https://doi.org/10.1101/gad.1941010.</ref>.

-	The '''histone tails residues''' can be [https://en.wikipedia.org/wiki/Acetylation acetylated], [https://en.wikipedia.org/wiki/Methylation methylated] or [https://en.wikipedia.org/wiki/Demethylation demethylated] by enzymes in order to modify chromatin state and therefore gene expression. Different types of proteins involved in this process exist, such as histone ~~acetylase~~ (HAT), histone ~~methylase~~ (HMT) or histone demethylase (HDM)<ref>Nasir Javaid, and Sangdun Choi. “Acetylation- and Methylation-Related Epigenetic Proteins in the Context of Their Targets.” Genes 8, no. 8 (August 7, 2017): 196. https://doi.org/10.3390/genes8080196</ref>.	+	The '''histone tails residues''' can be [https://en.wikipedia.org/wiki/Acetylation acetylated], [https://en.wikipedia.org/wiki/Methylation methylated] or [https://en.wikipedia.org/wiki/Demethylation demethylated] by enzymes in order to modify chromatin state and therefore gene expression. Different types of proteins involved in this process exist, such as histone acetyltransferase (HAT), histone methyltransferase (HMT) or histone demethylase (HDM)<ref>Nasir Javaid, and Sangdun Choi. “Acetylation- and Methylation-Related Epigenetic Proteins in the Context of Their Targets.” Genes 8, no. 8 (August 7, 2017): 196. https://doi.org/10.3390/genes8080196</ref>.

	Two families of [https://en.wikipedia.org/wiki/Demethylase histone-lysine demethylase] (KDM) have been identified as follows : the '''flavin (FAD)-dependent lysine-specific demethylases''' and the '''Fe(II)-dependent Jumonji C (JmjC) family'''. JmjC is subfamily of histone demethylases which regroups several proteins containing a specific catalytic domain called '''Jmjc''' found in ''' 2xml structure'''<ref>Shi, Y. G., and Y.-i. Tsukada. “The Discovery of Histone Demethylases.” Cold Spring Harbor Perspectives in Biology 5, no. 9 (September 1, 2013): a017947–a017947. https://doi.org/10.1101/cshperspect.a017947.</ref>. KDM4 demethylases belong to the JmjC family and contains six members : KDM4A-F<ref>Labbé, Roselyne M., Andreana Holowatyj, and Zeng-Quan Yang. “Histone Lysine Demethylase (KDM) Subfamily 4: Structures, Functions and Therapeutic Potential.” American Journal of Translational Research 6, no. 1 (2013): 1–15</ref>.		Two families of [https://en.wikipedia.org/wiki/Demethylase histone-lysine demethylase] (KDM) have been identified as follows : the '''flavin (FAD)-dependent lysine-specific demethylases''' and the '''Fe(II)-dependent Jumonji C (JmjC) family'''. JmjC is subfamily of histone demethylases which regroups several proteins containing a specific catalytic domain called '''Jmjc''' found in ''' 2xml structure'''<ref>Shi, Y. G., and Y.-i. Tsukada. “The Discovery of Histone Demethylases.” Cold Spring Harbor Perspectives in Biology 5, no. 9 (September 1, 2013): a017947–a017947. https://doi.org/10.1101/cshperspect.a017947.</ref>. KDM4 demethylases belong to the JmjC family and contains six members : KDM4A-F<ref>Labbé, Roselyne M., Andreana Holowatyj, and Zeng-Quan Yang. “Histone Lysine Demethylase (KDM) Subfamily 4: Structures, Functions and Therapeutic Potential.” American Journal of Translational Research 6, no. 1 (2013): 1–15</ref>.

Emeric Goetz at 17:10, 10 January 2019

Emeric Goetz — Thu, 10 Jan 2019 17:10:49 GMT

←Older revision		Revision as of 17:10, 10 January 2019
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	Two families of [https://en.wikipedia.org/wiki/Demethylase histone-lysine demethylase] (KDM) have been identified as follows : the '''flavin (FAD)-dependent lysine-specific demethylases''' and the '''Fe(II)-dependent Jumonji C (JmjC) family'''. JmjC is subfamily of histone demethylases which regroups several proteins containing a specific catalytic domain called '''Jmjc''' found in ''' 2xml structure'''<ref>Shi, Y. G., and Y.-i. Tsukada. “The Discovery of Histone Demethylases.” Cold Spring Harbor Perspectives in Biology 5, no. 9 (September 1, 2013): a017947–a017947. https://doi.org/10.1101/cshperspect.a017947.</ref>. KDM4 demethylases belong to the JmjC family and contains six members : KDM4A-F<ref>Labbé, Roselyne M., Andreana Holowatyj, and Zeng-Quan Yang. “Histone Lysine Demethylase (KDM) Subfamily 4: Structures, Functions and Therapeutic Potential.” American Journal of Translational Research 6, no. 1 (2013): 1–15</ref>.		Two families of [https://en.wikipedia.org/wiki/Demethylase histone-lysine demethylase] (KDM) have been identified as follows : the '''flavin (FAD)-dependent lysine-specific demethylases''' and the '''Fe(II)-dependent Jumonji C (JmjC) family'''. JmjC is subfamily of histone demethylases which regroups several proteins containing a specific catalytic domain called '''Jmjc''' found in ''' 2xml structure'''<ref>Shi, Y. G., and Y.-i. Tsukada. “The Discovery of Histone Demethylases.” Cold Spring Harbor Perspectives in Biology 5, no. 9 (September 1, 2013): a017947–a017947. https://doi.org/10.1101/cshperspect.a017947.</ref>. KDM4 demethylases belong to the JmjC family and contains six members : KDM4A-F<ref>Labbé, Roselyne M., Andreana Holowatyj, and Zeng-Quan Yang. “Histone Lysine Demethylase (KDM) Subfamily 4: Structures, Functions and Therapeutic Potential.” American Journal of Translational Research 6, no. 1 (2013): 1–15</ref>.

-	[[Image:Reactionjpg.jpg \| thumb \| ~~center~~=2 \| Enzymatic reaction of demethylation of H3K9(me3) and H3K36(me3) by KDM4C ]]	+	[[Image:Reactionjpg.jpg \| thumb \| upright=3,5 \| Enzymatic reaction of demethylation of H3K9(me3) and H3K36(me3) by KDM4C ]]
	'''KDM4C/JMJD2''' is a protein which converts specifically trimethylated histone residues to the dimethylated form. Indeed, it catalyzes the demethylation of both '''Lysine 9 and Lysine 36 of histone 3''' (respectively H3K9me3 and H3K36me3 by hydroxylation of the lysine methyl group. This reaction leads to a dissociation of the methyl group from the lysine histone tail. KDM4C employs [https://en.wikipedia.org/wiki/Alpha-Ketoglutaric_acid 2-oxoglutarate] (OG), Fe2+ and oxygen as cosubstrates to promote its enzymatic reaction, thus the '''dissociation of one methyl group'''<ref>Leurs, Ulrike, Brian Lohse, Kasper D. Rand, Shonoi Ming, Erik S. Riise, Philip A. Cole, Jesper L. Kristensen, and Rasmus P. Clausen. “Substrate- and Cofactor-Independent Inhibition of Histone Demethylase KDM4C.” ACS Chemical Biology 9, no. 9 (September 19, 2014): 2131–38. https://doi.org/10.1021/cb500374f.</ref>.		'''KDM4C/JMJD2''' is a protein which converts specifically trimethylated histone residues to the dimethylated form. Indeed, it catalyzes the demethylation of both '''Lysine 9 and Lysine 36 of histone 3''' (respectively H3K9me3 and H3K36me3 by hydroxylation of the lysine methyl group. This reaction leads to a dissociation of the methyl group from the lysine histone tail. KDM4C employs [https://en.wikipedia.org/wiki/Alpha-Ketoglutaric_acid 2-oxoglutarate] (OG), Fe2+ and oxygen as cosubstrates to promote its enzymatic reaction, thus the '''dissociation of one methyl group'''<ref>Leurs, Ulrike, Brian Lohse, Kasper D. Rand, Shonoi Ming, Erik S. Riise, Philip A. Cole, Jesper L. Kristensen, and Rasmus P. Clausen. “Substrate- and Cofactor-Independent Inhibition of Histone Demethylase KDM4C.” ACS Chemical Biology 9, no. 9 (September 19, 2014): 2131–38. https://doi.org/10.1021/cb500374f.</ref>.

Emeric Goetz at 16:58, 10 January 2019

Emeric Goetz — Thu, 10 Jan 2019 16:58:52 GMT

←Older revision		Revision as of 16:58, 10 January 2019
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	== Function ==		== Function ==

-	'''Genes expression''' is directly related to the '''condensation state''' of the [https://en.wikipedia.org/wiki/Chromatin chromatin]. Indeed, chromatin can be in the form of [https://en.wikipedia.org/wiki/Heterochromatin heterochromatin] (condensed form of DNA) or [https://en.wikipedia.org/wiki/Euchromatin euchromatin] (relaxed form of DNA) which correspond respectively to the transcriptionally silent and active forms of DNA. Chromatin is composed of DNA wrapped around [https://en.wikipedia.org/wiki/Histone histone] octamers forming nucleosomes<ref>Tamaru, H. “Confining Euchromatin/Heterochromatin Territory: Jumonji Crosses the Line.” Genes & Development 24, no. 14 (July 15, 2010): 1465–78. https://doi.org/10.1101/gad.1941010.</ref>. The '''histone tails residues''' can be [https://en.wikipedia.org/wiki/Acetylation acetylated], [https://en.wikipedia.org/wiki/Methylation methylated] or [https://en.wikipedia.org/wiki/Demethylation demethylated] by enzymes in order to modify chromatin state and therefore gene expression. Different types of proteins involved in this process exist, such as histone acetylase (HAT), histone methylase (HMT) or histone demethylase (HDM)<ref>Nasir Javaid, and Sangdun Choi. “Acetylation- and Methylation-Related Epigenetic Proteins in the Context of Their Targets.” Genes 8, no. 8 (August 7, 2017): 196. https://doi.org/10.3390/genes8080196</ref>.	+	'''Genes expression''' is directly related to the '''condensation state''' of the [https://en.wikipedia.org/wiki/Chromatin chromatin]. Indeed, chromatin can be in the form of [https://en.wikipedia.org/wiki/Heterochromatin heterochromatin] (condensed form of DNA) or [https://en.wikipedia.org/wiki/Euchromatin euchromatin] (relaxed form of DNA) which correspond respectively to the transcriptionally silent and active forms of DNA. Chromatin is composed of DNA wrapped around [https://en.wikipedia.org/wiki/Histone histone] octamers forming nucleosomes<ref>Tamaru, H. “Confining Euchromatin/Heterochromatin Territory: Jumonji Crosses the Line.” Genes & Development 24, no. 14 (July 15, 2010): 1465–78. https://doi.org/10.1101/gad.1941010.</ref>.
		+
		+	The '''histone tails residues''' can be [https://en.wikipedia.org/wiki/Acetylation acetylated], [https://en.wikipedia.org/wiki/Methylation methylated] or [https://en.wikipedia.org/wiki/Demethylation demethylated] by enzymes in order to modify chromatin state and therefore gene expression. Different types of proteins involved in this process exist, such as histone acetylase (HAT), histone methylase (HMT) or histone demethylase (HDM)<ref>Nasir Javaid, and Sangdun Choi. “Acetylation- and Methylation-Related Epigenetic Proteins in the Context of Their Targets.” Genes 8, no. 8 (August 7, 2017): 196. https://doi.org/10.3390/genes8080196</ref>.

	Two families of [https://en.wikipedia.org/wiki/Demethylase histone-lysine demethylase] (KDM) have been identified as follows : the '''flavin (FAD)-dependent lysine-specific demethylases''' and the '''Fe(II)-dependent Jumonji C (JmjC) family'''. JmjC is subfamily of histone demethylases which regroups several proteins containing a specific catalytic domain called '''Jmjc''' found in ''' 2xml structure'''<ref>Shi, Y. G., and Y.-i. Tsukada. “The Discovery of Histone Demethylases.” Cold Spring Harbor Perspectives in Biology 5, no. 9 (September 1, 2013): a017947–a017947. https://doi.org/10.1101/cshperspect.a017947.</ref>. KDM4 demethylases belong to the JmjC family and contains six members : KDM4A-F<ref>Labbé, Roselyne M., Andreana Holowatyj, and Zeng-Quan Yang. “Histone Lysine Demethylase (KDM) Subfamily 4: Structures, Functions and Therapeutic Potential.” American Journal of Translational Research 6, no. 1 (2013): 1–15</ref>.		Two families of [https://en.wikipedia.org/wiki/Demethylase histone-lysine demethylase] (KDM) have been identified as follows : the '''flavin (FAD)-dependent lysine-specific demethylases''' and the '''Fe(II)-dependent Jumonji C (JmjC) family'''. JmjC is subfamily of histone demethylases which regroups several proteins containing a specific catalytic domain called '''Jmjc''' found in ''' 2xml structure'''<ref>Shi, Y. G., and Y.-i. Tsukada. “The Discovery of Histone Demethylases.” Cold Spring Harbor Perspectives in Biology 5, no. 9 (September 1, 2013): a017947–a017947. https://doi.org/10.1101/cshperspect.a017947.</ref>. KDM4 demethylases belong to the JmjC family and contains six members : KDM4A-F<ref>Labbé, Roselyne M., Andreana Holowatyj, and Zeng-Quan Yang. “Histone Lysine Demethylase (KDM) Subfamily 4: Structures, Functions and Therapeutic Potential.” American Journal of Translational Research 6, no. 1 (2013): 1–15</ref>.

-	[[Image:Reactionjpg.jpg \| thumb \| ~~upright~~=3 \| Enzymatic reaction of demethylation of H3K9(me3) and H3K36(me3) by KDM4C ]]	+	[[Image:Reactionjpg.jpg \| thumb \| center=2 \| Enzymatic reaction of demethylation of H3K9(me3) and H3K36(me3) by KDM4C ]]
-	'''KDM4C/JMJD2''' is a protein which converts specifically trimethylated histone residues to the dimethylated form. Indeed, it catalyzes the demethylation of both '''Lysine 9 and Lysine 36 of histone 3''' (respectively H3K9me3 and H3K36me3 by hydroxylation of the lysine methyl group. This reaction leads to a dissociation of the methyl group from the lysine histone tail.	+	'''KDM4C/JMJD2''' is a protein which converts specifically trimethylated histone residues to the dimethylated form. Indeed, it catalyzes the demethylation of both '''Lysine 9 and Lysine 36 of histone 3''' (respectively H3K9me3 and H3K36me3 by hydroxylation of the lysine methyl group. This reaction leads to a dissociation of the methyl group from the lysine histone tail. KDM4C employs [https://en.wikipedia.org/wiki/Alpha-Ketoglutaric_acid 2-oxoglutarate] (OG), Fe2+ and oxygen as cosubstrates to promote its enzymatic reaction, thus the '''dissociation of one methyl group'''<ref>Leurs, Ulrike, Brian Lohse, Kasper D. Rand, Shonoi Ming, Erik S. Riise, Philip A. Cole, Jesper L. Kristensen, and Rasmus P. Clausen. “Substrate- and Cofactor-Independent Inhibition of Histone Demethylase KDM4C.” ACS Chemical Biology 9, no. 9 (September 19, 2014): 2131–38. https://doi.org/10.1021/cb500374f.</ref>.
-		+
-	KDM4C employs [https://en.wikipedia.org/wiki/Alpha-Ketoglutaric_acid 2-oxoglutarate] (OG), Fe2+ and oxygen as cosubstrates to promote its enzymatic reaction, thus the '''dissociation of one methyl group'''<ref>Leurs, Ulrike, Brian Lohse, Kasper D. Rand, Shonoi Ming, Erik S. Riise, Philip A. Cole, Jesper L. Kristensen, and Rasmus P. Clausen. “Substrate- and Cofactor-Independent Inhibition of Histone Demethylase KDM4C.” ACS Chemical Biology 9, no. 9 (September 19, 2014): 2131–38. https://doi.org/10.1021/cb500374f.</ref>.	+


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	For all the implications of KDM4C in different cancers, it is one of the main '''targets of anti-cancer treatments'''.		For all the implications of KDM4C in different cancers, it is one of the main '''targets of anti-cancer treatments'''.
-
-
-
-

	</StructureSection>		</StructureSection>
	== References ==		== References ==
	<references/>		<references/>

Emeric Goetz at 16:56, 10 January 2019

Emeric Goetz — Thu, 10 Jan 2019 16:56:02 GMT

←Older revision		Revision as of 16:56, 10 January 2019
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	- <scene name='80/802665/Cl/1'>Cl-</scene> : one binding site, only in chain A.		- <scene name='80/802665/Cl/1'>Cl-</scene> : one binding site, only in chain A.
-

	2xml presents, in each of the two chains, parallel [https://en.wikipedia.org/wiki/Beta_sheet β sheets] around <scene name='80/802665/Oga_pocket/1'>OGA</scene>, forming an '''hydrophobic pocket''' (mainly made of aromatic acid). OGA interacts with 2xml amino acids through hydrogen bonds and coordination bonds with Ni2+.		2xml presents, in each of the two chains, parallel [https://en.wikipedia.org/wiki/Beta_sheet β sheets] around <scene name='80/802665/Oga_pocket/1'>OGA</scene>, forming an '''hydrophobic pocket''' (mainly made of aromatic acid). OGA interacts with 2xml amino acids through hydrogen bonds and coordination bonds with Ni2+.
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	== Epigenetics ==		== Epigenetics ==

-	Specific enzymes are directly involved in the '''modification of genes expression''' without altering the nucleotide sequence. They can modify the chromatin structure by '''adding''' (writers), '''reading''' (readers) or '''removing''' (erasers) marks : acetyl, methyl, phosphoryl groups, ubiquitin<ref>Kupershmit, Ilana, Hanan Khoury-Haddad, Samah W. Awwad, Noga Guttmann-Raviv, and Nabieh Ayoub. “KDM4C (GASC1) Lysine Demethylase Is Associated with Mitotic Chromatin and Regulates Chromosome Segregation during Mitosis.” Nucleic Acids Research 42, no. 10 (June 2, 2014): 6168–82. https://doi.org/10.1093/nar/gku253.</ref>... These [https://en.wikipedia.org/wiki/Epigenetics epigenetic]marks can either make the gene sequence more or less accessible depending on their nature, histones and labelled amino acids. All combinations of the nature and the localization of the marks form the histone code.	+	Specific enzymes are directly involved in the '''modification of genes expression''' without altering the nucleotide sequence. They can modify the chromatin structure by '''adding''' (writers), '''reading''' (readers) or '''removing''' (erasers) marks : acetyl, methyl, phosphoryl groups, ubiquitin<ref>Kupershmit, Ilana, Hanan Khoury-Haddad, Samah W. Awwad, Noga Guttmann-Raviv, and Nabieh Ayoub. “KDM4C (GASC1) Lysine Demethylase Is Associated with Mitotic Chromatin and Regulates Chromosome Segregation during Mitosis.” Nucleic Acids Research 42, no. 10 (June 2, 2014): 6168–82. https://doi.org/10.1093/nar/gku253.</ref>... These [https://en.wikipedia.org/wiki/Epigenetics epigenetic]marks can either make the gene sequence more or less accessible for [https://en.wikipedia.org/wiki/Transcription_factor transcription factors] depending on their nature, histones and labelled amino acids. All combinations of the nature and the localization of the marks form the [https://en.wikipedia.org/wiki/Histone_code histone code].
		+
		+	KDM4C is a histone demethylase. This newly discovered class of proteins plays a central role in the '''epigenetic modifications''' : it removes the methyl group (which is very stable) from the epigenetically modified amino acid. Its actions has directed consequences on gene expression. By removing the third methyl group from '''Lysine 9 of histone 3''' (H3K9me3), KDM4C promotes the formation of euchromatin and therefore '''transcriptional activation'''. However, KDM4C indirectly condenses chromatin by removing the third methyl group from '''Lysine 36 of histone 3''' (H3K36me3), leading to a '''repression of target genes expression'''<ref>Berry, W. L., and R. Janknecht. “KDM4/JMJD2 Histone Demethylases: Epigenetic Regulators in Cancer Cells.” Cancer Research 73, no. 10 (May 15, 2013): 2936–42.</ref>.

-	KDM4C is a histone demethylase. This newly discovered class of proteins plays a central role in the histone modifications : it removes the methyl group (which is very stable) from the epigenetically modified amino acid. Its actions has directed consequences on gene expression. By removing repressive histone marks (H3K9me3 and H3K36me3) from target genes KDM4C promotes the formation of euchromatin and therefore transcriptional activation.

	== Disease ==		== Disease ==
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	- Ability to invade the body and other organs. <ref>Douglas Hanahan et Robert A. Weinberg, « The hallmarks of cancer », Cell, vol. 100,‎ 7 janvier 2000, p. 57-70 (PMID 10647931)</ref>		- Ability to invade the body and other organs. <ref>Douglas Hanahan et Robert A. Weinberg, « The hallmarks of cancer », Cell, vol. 100,‎ 7 janvier 2000, p. 57-70 (PMID 10647931)</ref>
-

	The development of cancer begins with the modification of the sequence and expression of the genes involved in the [https://en.wikipedia.org/wiki/Cell_cycle cell cycle]. <ref>https://en.wikipedia.org/wiki/Cancer</ref>		The development of cancer begins with the modification of the sequence and expression of the genes involved in the [https://en.wikipedia.org/wiki/Cell_cycle cell cycle]. <ref>https://en.wikipedia.org/wiki/Cancer</ref>

	The transformation from healthy cells to cancer cells is carried out in two stages: '''carcinogenesis and tumorigenesis'''.		The transformation from healthy cells to cancer cells is carried out in two stages: '''carcinogenesis and tumorigenesis'''.
		+
	During [https://en.wikipedia.org/wiki/Carcinogenesis carcinogenesis], cells accumulate '''genetic abnormalities''', particularly in [https://en.wikipedia.org/wiki/Oncogene oncogenic] sequences. '''Oncogenes''' are positive regulators of cell proliferation. After a mutation, they become hyperactive and cause an excessive cellular growth. [https://en.wikipedia.org/wiki/Caretaker_gene '''Gatekeeper genes'''] (genes that allow the passage from one stage of the cell cycle to the next) can also be mutated, leading to uncontrolled cell proliferation.		During [https://en.wikipedia.org/wiki/Carcinogenesis carcinogenesis], cells accumulate '''genetic abnormalities''', particularly in [https://en.wikipedia.org/wiki/Oncogene oncogenic] sequences. '''Oncogenes''' are positive regulators of cell proliferation. After a mutation, they become hyperactive and cause an excessive cellular growth. [https://en.wikipedia.org/wiki/Caretaker_gene '''Gatekeeper genes'''] (genes that allow the passage from one stage of the cell cycle to the next) can also be mutated, leading to uncontrolled cell proliferation.
		+
	During tumorigenesis, cancer becomes invasive: cancer cells invade other healthy organs.		During tumorigenesis, cancer becomes invasive: cancer cells invade other healthy organs.
-

	KDM4C is involved in carcinogenesis as an oncogene. Indeed, by catalyzing the demethylation of H3K9-me3 (lysine 9 from trimethylated histones 3) to H3K9-me2 (lysine 9 from dimethylated histones 3), this protein increases the expression of its target genes. Several KDM4C target genes are involved in [https://en.wikipedia.org/wiki/Cell_growth cell growth]. For example, they influence mitogenic signalling - which promotes mitosis and cell division -, cell cycle regulation and translation.		KDM4C is involved in carcinogenesis as an oncogene. Indeed, by catalyzing the demethylation of H3K9-me3 (lysine 9 from trimethylated histones 3) to H3K9-me2 (lysine 9 from dimethylated histones 3), this protein increases the expression of its target genes. Several KDM4C target genes are involved in [https://en.wikipedia.org/wiki/Cell_growth cell growth]. For example, they influence mitogenic signalling - which promotes mitosis and cell division -, cell cycle regulation and translation.
	In cancer cells, KDM4C expression is enhanced. Thus, the growth of tumor cells is greatly increased. <ref>Gregory, Brittany L., and Vivian G. Cheung. ‘Natural Variation in the Histone Demethylase, KDM4C, Influences Expression Levels of Specific Genes Including Those That Affect Cell Growth’. Genome Research 24, no. 1 (January 2014): 52–63. https://doi.org/10.1101/gr.156141.113</ref>		In cancer cells, KDM4C expression is enhanced. Thus, the growth of tumor cells is greatly increased. <ref>Gregory, Brittany L., and Vivian G. Cheung. ‘Natural Variation in the Histone Demethylase, KDM4C, Influences Expression Levels of Specific Genes Including Those That Affect Cell Growth’. Genome Research 24, no. 1 (January 2014): 52–63. https://doi.org/10.1101/gr.156141.113</ref>
-

	In addition, KDM4C is involved in the correct [https://en.wikipedia.org/wiki/Chromosome_segregation segregation of chromosomes]. Its high presence in tumor cells therefore ensures their viability.<ref>Garcia, Jeison, and Fernando Lizcano. ‘KDM4C Activity Modulates Cell Proliferation and Chromosome Segregation in Triple-Negative Breast Cancer’. Breast Cancer : Basic and Clinical Research 10 (2 November 2016): 169–75. https://doi.org/10.4137/BCBCR.S40182.</ref>		In addition, KDM4C is involved in the correct [https://en.wikipedia.org/wiki/Chromosome_segregation segregation of chromosomes]. Its high presence in tumor cells therefore ensures their viability.<ref>Garcia, Jeison, and Fernando Lizcano. ‘KDM4C Activity Modulates Cell Proliferation and Chromosome Segregation in Triple-Negative Breast Cancer’. Breast Cancer : Basic and Clinical Research 10 (2 November 2016): 169–75. https://doi.org/10.4137/BCBCR.S40182.</ref>

	Finally, KDM4C also plays a role in the tumorigenesis of certain cancers, such as '''breast cancer''', since it allows the proliferation of cancer cells, their migration and their invasive capacity in the triple-negative breast cancer.		Finally, KDM4C also plays a role in the tumorigenesis of certain cancers, such as '''breast cancer''', since it allows the proliferation of cancer cells, their migration and their invasive capacity in the triple-negative breast cancer.
-

	For all the implications of KDM4C in different cancers, it is one of the main '''targets of anti-cancer treatments'''.		For all the implications of KDM4C in different cancers, it is one of the main '''targets of anti-cancer treatments'''.
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-	This is a sample scene created with SAT to <scene name="/12/3456/Sample/1">color</scene> by Group, and another to make <scene name="/12/3456/Sample/2">a transparent representation</scene> of the protein. You can make your own scenes on SAT starting from scratch or loading and editing one of these sample scenes.	+

	</StructureSection>		</StructureSection>
	== References ==		== References ==
	<references/>		<references/>

Emeric Goetz at 16:41, 10 January 2019

Emeric Goetz — Thu, 10 Jan 2019 16:41:41 GMT

←Older revision		Revision as of 16:41, 10 January 2019
Line 42:		Line 42:
	The sequence of the domain has been particularly preserved around OGA (when the protein is folded)<ref>http://consurf.tau.ac.il/fgij/fg.htm?mol=/temp/2XMLA_ConSurf_DB_pipe.pdb </ref>. Thus, the 3D structure has been very preserved as well, indicating that the structure around OGA is essential.		The sequence of the domain has been particularly preserved around OGA (when the protein is folded)<ref>http://consurf.tau.ac.il/fgij/fg.htm?mol=/temp/2XMLA_ConSurf_DB_pipe.pdb </ref>. Thus, the 3D structure has been very preserved as well, indicating that the structure around OGA is essential.

-	== ~~Epigenetic~~ ==	+	== Epigenetics ==

-	Specific enzymes are directly involved in the modification of genes expression without altering the nucleotide sequence. They can modify the chromatin structure by adding (writers), reading (readers) or removing (erasers) marks : ~~acetylation~~, ~~methylation~~, ~~phosphorylation~~, ~~ubiquitination~~, ~~sumoylation~~... These marks can either make the gene sequence more or less accessible depending on their nature, histones and labelled amino acids. All combinations of the nature and the localization of the marks form the histone code.	+	Specific enzymes are directly involved in the '''modification of genes expression''' without altering the nucleotide sequence. They can modify the chromatin structure by '''adding''' (writers), '''reading''' (readers) or '''removing''' (erasers) marks : acetyl, methyl, phosphoryl groups, ubiquitin<ref>Kupershmit, Ilana, Hanan Khoury-Haddad, Samah W. Awwad, Noga Guttmann-Raviv, and Nabieh Ayoub. “KDM4C (GASC1) Lysine Demethylase Is Associated with Mitotic Chromatin and Regulates Chromosome Segregation during Mitosis.” Nucleic Acids Research 42, no. 10 (June 2, 2014): 6168–82. https://doi.org/10.1093/nar/gku253.</ref>... These [https://en.wikipedia.org/wiki/Epigenetics epigenetic]marks can either make the gene sequence more or less accessible depending on their nature, histones and labelled amino acids. All combinations of the nature and the localization of the marks form the histone code.

	KDM4C is a histone demethylase. This newly discovered class of proteins plays a central role in the histone modifications : it removes the methyl group (which is very stable) from the epigenetically modified amino acid. Its actions has directed consequences on gene expression. By removing repressive histone marks (H3K9me3 and H3K36me3) from target genes KDM4C promotes the formation of euchromatin and therefore transcriptional activation.		KDM4C is a histone demethylase. This newly discovered class of proteins plays a central role in the histone modifications : it removes the methyl group (which is very stable) from the epigenetically modified amino acid. Its actions has directed consequences on gene expression. By removing repressive histone marks (H3K9me3 and H3K36me3) from target genes KDM4C promotes the formation of euchromatin and therefore transcriptional activation.

Emeric Goetz at 16:37, 10 January 2019

Emeric Goetz — Thu, 10 Jan 2019 16:37:06 GMT

←Older revision		Revision as of 16:37, 10 January 2019
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	'''KDM4C/JMJD2''' is a protein which converts specifically trimethylated histone residues to the dimethylated form. Indeed, it catalyzes the demethylation of both '''Lysine 9 and Lysine 36 of histone 3''' (respectively H3K9me3 and H3K36me3 by hydroxylation of the lysine methyl group. This reaction leads to a dissociation of the methyl group from the lysine histone tail.		'''KDM4C/JMJD2''' is a protein which converts specifically trimethylated histone residues to the dimethylated form. Indeed, it catalyzes the demethylation of both '''Lysine 9 and Lysine 36 of histone 3''' (respectively H3K9me3 and H3K36me3 by hydroxylation of the lysine methyl group. This reaction leads to a dissociation of the methyl group from the lysine histone tail.

-	KDM4C employs [https://en.wikipedia.org/wiki/Alpha-Ketoglutaric_acid 2-oxoglutarate] (OG), Fe2+ and oxygen as cosubstrates to promote its enzymatic reaction, thus the '''dissociation of methyl ~~groups~~'''<ref>Leurs, Ulrike, Brian Lohse, Kasper D. Rand, Shonoi Ming, Erik S. Riise, Philip A. Cole, Jesper L. Kristensen, and Rasmus P. Clausen. “Substrate- and Cofactor-Independent Inhibition of Histone Demethylase KDM4C.” ACS Chemical Biology 9, no. 9 (September 19, 2014): 2131–38. https://doi.org/10.1021/cb500374f.</ref>.	+	KDM4C employs [https://en.wikipedia.org/wiki/Alpha-Ketoglutaric_acid 2-oxoglutarate] (OG), Fe2+ and oxygen as cosubstrates to promote its enzymatic reaction, thus the '''dissociation of one methyl group'''<ref>Leurs, Ulrike, Brian Lohse, Kasper D. Rand, Shonoi Ming, Erik S. Riise, Philip A. Cole, Jesper L. Kristensen, and Rasmus P. Clausen. “Substrate- and Cofactor-Independent Inhibition of Histone Demethylase KDM4C.” ACS Chemical Biology 9, no. 9 (September 19, 2014): 2131–38. https://doi.org/10.1021/cb500374f.</ref>.

Emeric Goetz at 16:35, 10 January 2019

Emeric Goetz — Thu, 10 Jan 2019 16:35:26 GMT

←Older revision		Revision as of 16:35, 10 January 2019
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	[[Image:Reactionjpg.jpg \| thumb \| upright=3 \| Enzymatic reaction of demethylation of H3K9(me3) and H3K36(me3) by KDM4C ]]		[[Image:Reactionjpg.jpg \| thumb \| upright=3 \| Enzymatic reaction of demethylation of H3K9(me3) and H3K36(me3) by KDM4C ]]
-	'''KDM4C/JMJD2''' is a protein which converts specifically trimethylated histone residues to the dimethylated form. Indeed, it catalyzes the demethylation of both '''Lysine 9 and Lysine 36 of histone 3''' (respectively H3K9me3 and H3K36me3 by hydroxylation of the lysine methyl group. This reaction leads to a dissociation of the methyl group from the lysine histone tail. KDM4C employs [https://en.wikipedia.org/wiki/Alpha-Ketoglutaric_acid 2-oxoglutarate] (OG), Fe2+ and oxygen as cosubstrates to promote its enzymatic reaction, thus the '''dissociation of methyl groups'''<ref>Leurs, Ulrike, Brian Lohse, Kasper D. Rand, Shonoi Ming, Erik S. Riise, Philip A. Cole, Jesper L. Kristensen, and Rasmus P. Clausen. “Substrate- and Cofactor-Independent Inhibition of Histone Demethylase KDM4C.” ACS Chemical Biology 9, no. 9 (September 19, 2014): 2131–38. https://doi.org/10.1021/cb500374f.</ref>.	+	'''KDM4C/JMJD2''' is a protein which converts specifically trimethylated histone residues to the dimethylated form. Indeed, it catalyzes the demethylation of both '''Lysine 9 and Lysine 36 of histone 3''' (respectively H3K9me3 and H3K36me3 by hydroxylation of the lysine methyl group. This reaction leads to a dissociation of the methyl group from the lysine histone tail.
		+
		+	KDM4C employs [https://en.wikipedia.org/wiki/Alpha-Ketoglutaric_acid 2-oxoglutarate] (OG), Fe2+ and oxygen as cosubstrates to promote its enzymatic reaction, thus the '''dissociation of methyl groups'''<ref>Leurs, Ulrike, Brian Lohse, Kasper D. Rand, Shonoi Ming, Erik S. Riise, Philip A. Cole, Jesper L. Kristensen, and Rasmus P. Clausen. “Substrate- and Cofactor-Independent Inhibition of Histone Demethylase KDM4C.” ACS Chemical Biology 9, no. 9 (September 19, 2014): 2131–38. https://doi.org/10.1021/cb500374f.</ref>.

Emeric Goetz at 16:33, 10 January 2019

Emeric Goetz — Thu, 10 Jan 2019 16:33:01 GMT

←Older revision		Revision as of 16:33, 10 January 2019
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	[[Image:Reactionjpg.jpg \| thumb \| upright=3 \| Enzymatic reaction of demethylation of H3K9(me3) and H3K36(me3) by KDM4C ]]		[[Image:Reactionjpg.jpg \| thumb \| upright=3 \| Enzymatic reaction of demethylation of H3K9(me3) and H3K36(me3) by KDM4C ]]
-	'''KDM4C/JMJD2''' is a protein which converts ~~specific~~ trimethylated histone residues to the dimethylated form. Indeed, it catalyzes the demethylation of both '''Lysine 9 and Lysine 36 of histone 3''' (respectively H3K9me3 and H3K36me3 by hydroxylation of the lysine methyl group. This reaction leads to a dissociation of the methyl group from the lysine histone tail. KDM4C employs (OG), Fe2+ and oxygen as cosubstrates to promote its enzymatic reaction, thus the '''dissociation of methyl groups'''.	+	'''KDM4C/JMJD2''' is a protein which converts specifically trimethylated histone residues to the dimethylated form. Indeed, it catalyzes the demethylation of both '''Lysine 9 and Lysine 36 of histone 3''' (respectively H3K9me3 and H3K36me3 by hydroxylation of the lysine methyl group. This reaction leads to a dissociation of the methyl group from the lysine histone tail. KDM4C employs [https://en.wikipedia.org/wiki/Alpha-Ketoglutaric_acid 2-oxoglutarate] (OG), Fe2+ and oxygen as cosubstrates to promote its enzymatic reaction, thus the '''dissociation of methyl groups'''<ref>Leurs, Ulrike, Brian Lohse, Kasper D. Rand, Shonoi Ming, Erik S. Riise, Philip A. Cole, Jesper L. Kristensen, and Rasmus P. Clausen. “Substrate- and Cofactor-Independent Inhibition of Histone Demethylase KDM4C.” ACS Chemical Biology 9, no. 9 (September 19, 2014): 2131–38. https://doi.org/10.1021/cb500374f.</ref>.

Emeric Goetz at 16:29, 10 January 2019

Emeric Goetz — Thu, 10 Jan 2019 16:29:07 GMT

←Older revision		Revision as of 16:29, 10 January 2019
Line 14:		Line 14:
	'''Genes expression''' is directly related to the '''condensation state''' of the [https://en.wikipedia.org/wiki/Chromatin chromatin]. Indeed, chromatin can be in the form of [https://en.wikipedia.org/wiki/Heterochromatin heterochromatin] (condensed form of DNA) or [https://en.wikipedia.org/wiki/Euchromatin euchromatin] (relaxed form of DNA) which correspond respectively to the transcriptionally silent and active forms of DNA. Chromatin is composed of DNA wrapped around [https://en.wikipedia.org/wiki/Histone histone] octamers forming nucleosomes<ref>Tamaru, H. “Confining Euchromatin/Heterochromatin Territory: Jumonji Crosses the Line.” Genes & Development 24, no. 14 (July 15, 2010): 1465–78. https://doi.org/10.1101/gad.1941010.</ref>. The '''histone tails residues''' can be [https://en.wikipedia.org/wiki/Acetylation acetylated], [https://en.wikipedia.org/wiki/Methylation methylated] or [https://en.wikipedia.org/wiki/Demethylation demethylated] by enzymes in order to modify chromatin state and therefore gene expression. Different types of proteins involved in this process exist, such as histone acetylase (HAT), histone methylase (HMT) or histone demethylase (HDM)<ref>Nasir Javaid, and Sangdun Choi. “Acetylation- and Methylation-Related Epigenetic Proteins in the Context of Their Targets.” Genes 8, no. 8 (August 7, 2017): 196. https://doi.org/10.3390/genes8080196</ref>.		'''Genes expression''' is directly related to the '''condensation state''' of the [https://en.wikipedia.org/wiki/Chromatin chromatin]. Indeed, chromatin can be in the form of [https://en.wikipedia.org/wiki/Heterochromatin heterochromatin] (condensed form of DNA) or [https://en.wikipedia.org/wiki/Euchromatin euchromatin] (relaxed form of DNA) which correspond respectively to the transcriptionally silent and active forms of DNA. Chromatin is composed of DNA wrapped around [https://en.wikipedia.org/wiki/Histone histone] octamers forming nucleosomes<ref>Tamaru, H. “Confining Euchromatin/Heterochromatin Territory: Jumonji Crosses the Line.” Genes & Development 24, no. 14 (July 15, 2010): 1465–78. https://doi.org/10.1101/gad.1941010.</ref>. The '''histone tails residues''' can be [https://en.wikipedia.org/wiki/Acetylation acetylated], [https://en.wikipedia.org/wiki/Methylation methylated] or [https://en.wikipedia.org/wiki/Demethylation demethylated] by enzymes in order to modify chromatin state and therefore gene expression. Different types of proteins involved in this process exist, such as histone acetylase (HAT), histone methylase (HMT) or histone demethylase (HDM)<ref>Nasir Javaid, and Sangdun Choi. “Acetylation- and Methylation-Related Epigenetic Proteins in the Context of Their Targets.” Genes 8, no. 8 (August 7, 2017): 196. https://doi.org/10.3390/genes8080196</ref>.

-	Two families of [https://en.wikipedia.org/wiki/Demethylase histone-lysine demethylase] (KDM) have been identified as follows : the '''flavin (FAD)-dependent lysine-specific demethylases''' and the '''Fe(II)-dependent Jumonji C (JmjC) family'''. JmjC is subfamily of histone demethylases which regroups several proteins containing a specific catalytic domain called '''Jmjc''' found in ''' 2xml structure'''. KDM4 demethylases belong to the JmjC family and contains six members : KDM4A-F<ref>Labbé, Roselyne M., Andreana Holowatyj, and Zeng-Quan Yang. “Histone Lysine Demethylase (KDM) Subfamily 4: Structures, Functions and Therapeutic Potential.” American Journal of Translational Research 6, no. 1 (2013): 1–15</ref>.	+	Two families of [https://en.wikipedia.org/wiki/Demethylase histone-lysine demethylase] (KDM) have been identified as follows : the '''flavin (FAD)-dependent lysine-specific demethylases''' and the '''Fe(II)-dependent Jumonji C (JmjC) family'''. JmjC is subfamily of histone demethylases which regroups several proteins containing a specific catalytic domain called '''Jmjc''' found in ''' 2xml structure'''<ref>Shi, Y. G., and Y.-i. Tsukada. “The Discovery of Histone Demethylases.” Cold Spring Harbor Perspectives in Biology 5, no. 9 (September 1, 2013): a017947–a017947. https://doi.org/10.1101/cshperspect.a017947.</ref>. KDM4 demethylases belong to the JmjC family and contains six members : KDM4A-F<ref>Labbé, Roselyne M., Andreana Holowatyj, and Zeng-Quan Yang. “Histone Lysine Demethylase (KDM) Subfamily 4: Structures, Functions and Therapeutic Potential.” American Journal of Translational Research 6, no. 1 (2013): 1–15</ref>.

	[[Image:Reactionjpg.jpg \| thumb \| upright=3 \| Enzymatic reaction of demethylation of H3K9(me3) and H3K36(me3) by KDM4C ]]		[[Image:Reactionjpg.jpg \| thumb \| upright=3 \| Enzymatic reaction of demethylation of H3K9(me3) and H3K36(me3) by KDM4C ]]

Emeric Goetz at 16:27, 10 January 2019

Emeric Goetz — Thu, 10 Jan 2019 16:27:08 GMT

←Older revision		Revision as of 16:27, 10 January 2019
Line 14:		Line 14:
	'''Genes expression''' is directly related to the '''condensation state''' of the [https://en.wikipedia.org/wiki/Chromatin chromatin]. Indeed, chromatin can be in the form of [https://en.wikipedia.org/wiki/Heterochromatin heterochromatin] (condensed form of DNA) or [https://en.wikipedia.org/wiki/Euchromatin euchromatin] (relaxed form of DNA) which correspond respectively to the transcriptionally silent and active forms of DNA. Chromatin is composed of DNA wrapped around [https://en.wikipedia.org/wiki/Histone histone] octamers forming nucleosomes<ref>Tamaru, H. “Confining Euchromatin/Heterochromatin Territory: Jumonji Crosses the Line.” Genes & Development 24, no. 14 (July 15, 2010): 1465–78. https://doi.org/10.1101/gad.1941010.</ref>. The '''histone tails residues''' can be [https://en.wikipedia.org/wiki/Acetylation acetylated], [https://en.wikipedia.org/wiki/Methylation methylated] or [https://en.wikipedia.org/wiki/Demethylation demethylated] by enzymes in order to modify chromatin state and therefore gene expression. Different types of proteins involved in this process exist, such as histone acetylase (HAT), histone methylase (HMT) or histone demethylase (HDM)<ref>Nasir Javaid, and Sangdun Choi. “Acetylation- and Methylation-Related Epigenetic Proteins in the Context of Their Targets.” Genes 8, no. 8 (August 7, 2017): 196. https://doi.org/10.3390/genes8080196</ref>.		'''Genes expression''' is directly related to the '''condensation state''' of the [https://en.wikipedia.org/wiki/Chromatin chromatin]. Indeed, chromatin can be in the form of [https://en.wikipedia.org/wiki/Heterochromatin heterochromatin] (condensed form of DNA) or [https://en.wikipedia.org/wiki/Euchromatin euchromatin] (relaxed form of DNA) which correspond respectively to the transcriptionally silent and active forms of DNA. Chromatin is composed of DNA wrapped around [https://en.wikipedia.org/wiki/Histone histone] octamers forming nucleosomes<ref>Tamaru, H. “Confining Euchromatin/Heterochromatin Territory: Jumonji Crosses the Line.” Genes & Development 24, no. 14 (July 15, 2010): 1465–78. https://doi.org/10.1101/gad.1941010.</ref>. The '''histone tails residues''' can be [https://en.wikipedia.org/wiki/Acetylation acetylated], [https://en.wikipedia.org/wiki/Methylation methylated] or [https://en.wikipedia.org/wiki/Demethylation demethylated] by enzymes in order to modify chromatin state and therefore gene expression. Different types of proteins involved in this process exist, such as histone acetylase (HAT), histone methylase (HMT) or histone demethylase (HDM)<ref>Nasir Javaid, and Sangdun Choi. “Acetylation- and Methylation-Related Epigenetic Proteins in the Context of Their Targets.” Genes 8, no. 8 (August 7, 2017): 196. https://doi.org/10.3390/genes8080196</ref>.

-	Two families of [https://en.wikipedia.org/wiki/Demethylase histone-lysine demethylase] (KDM) have been identified as follows : the '''flavin (FAD)-dependent lysine-specific demethylases''' and the '''Fe(II)-dependent Jumonji C (JmjC) family'''. JmjC is subfamily of histone demethylases which regroups several proteins containing a specific catalytic domain called '''Jmjc''' found in ''' 2xml structure'''. KDM4 demethylases belong to the JmjC family and contains six members : KDM4A-F	+	Two families of [https://en.wikipedia.org/wiki/Demethylase histone-lysine demethylase] (KDM) have been identified as follows : the '''flavin (FAD)-dependent lysine-specific demethylases''' and the '''Fe(II)-dependent Jumonji C (JmjC) family'''. JmjC is subfamily of histone demethylases which regroups several proteins containing a specific catalytic domain called '''Jmjc''' found in ''' 2xml structure'''. KDM4 demethylases belong to the JmjC family and contains six members : KDM4A-F<ref>Labbé, Roselyne M., Andreana Holowatyj, and Zeng-Quan Yang. “Histone Lysine Demethylase (KDM) Subfamily 4: Structures, Functions and Therapeutic Potential.” American Journal of Translational Research 6, no. 1 (2013): 1–15</ref>.

	[[Image:Reactionjpg.jpg \| thumb \| upright=3 \| Enzymatic reaction of demethylation of H3K9(me3) and H3K36(me3) by KDM4C ]]		[[Image:Reactionjpg.jpg \| thumb \| upright=3 \| Enzymatic reaction of demethylation of H3K9(me3) and H3K36(me3) by KDM4C ]]