Physical and Functional Association of a Trimethyl H3K4 Demethylase and Ring6a/MBLR, a Polycomb-like Protein

Min Gyu Lee; Jessica Norman; Ali Shilatifard; Ramin Shiekhattar

doi:10.1016/j.cell.2007.02.004

Physical and Functional Association of a Trimethyl H3K4 Demethylase and Ring6a/MBLR, a Polycomb-like Protein

Min Gyu Lee, Jessica Norman, Ali Shilatifard, Ramin Shiekhattar^*

^*Corresponding author for this work

Biochemistry and Molecular Genetics

Research output: Contribution to journal › Article › peer-review

216 Scopus citations

Abstract

Histone methylation is a posttranslational modification regulating chromatin structure and gene regulation. BHC110/LSD1 was the first histone demethylase described to reverse dimethyl histone H3 lysine 4 (H3K4). Here we show that JARID1d, a JmjC-domain-containing protein, specifically demethylates trimethyl H3K4. Detailed mapping analysis revealed that besides the JmjC domain, the BRIGHT and zinc-finger-like C₅HC₂ domains are required for maximum catalytic activity. Importantly, isolation of native JARID1d complexes from human cells revealed the association of the demethylase with a polycomb-like protein Ring6a/MBLR. Ring6a/MBLR not only directly interacts with JARID1d but also regulates its enzymatic activity. We show that JARID1d and Ring6a occupy human Engrailed 2 gene and regulate its expression and H3K4 methylation levels. Depletion of JARID1d enhanced recruitment of the chromatin remodeling complex, NURF, and the basal transcription machinery near the transcriptional start site, revealing a role for JARID1d in regulation of transcriptional initiation through H3K4 demethylation.

Original language	English (US)
Pages (from-to)	877-887
Number of pages	11
Journal	Cell
Volume	128
Issue number	5
DOIs	https://doi.org/10.1016/j.cell.2007.02.004
State	Published - Mar 9 2007

Funding

We thank Drs. D. Reinberg, T. Jenuwein, and H. Koga for their antibodies; Dr. D. Bochar for recombinant AOF1; and Kazusa DNA Research Institute Foundation for KIAA0234 cDNA. We extend our gratitude to Drs. D. Baillat, C. Wynder, S. McMahon, and X. Zhang for helpful advice and technical assistance; to Henry Hoff for protein expression; and to Matt Hart, Tom Beer, Kaye Speicher, and Dr. D. Speicher for help with mass spectrometry. R.S. was supported by a grant from NIH RO1CA090758.

ASJC Scopus subject areas

General Biochemistry, Genetics and Molecular Biology

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10.1016/j.cell.2007.02.004

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title = "Physical and Functional Association of a Trimethyl H3K4 Demethylase and Ring6a/MBLR, a Polycomb-like Protein",

abstract = "Histone methylation is a posttranslational modification regulating chromatin structure and gene regulation. BHC110/LSD1 was the first histone demethylase described to reverse dimethyl histone H3 lysine 4 (H3K4). Here we show that JARID1d, a JmjC-domain-containing protein, specifically demethylates trimethyl H3K4. Detailed mapping analysis revealed that besides the JmjC domain, the BRIGHT and zinc-finger-like C5HC2 domains are required for maximum catalytic activity. Importantly, isolation of native JARID1d complexes from human cells revealed the association of the demethylase with a polycomb-like protein Ring6a/MBLR. Ring6a/MBLR not only directly interacts with JARID1d but also regulates its enzymatic activity. We show that JARID1d and Ring6a occupy human Engrailed 2 gene and regulate its expression and H3K4 methylation levels. Depletion of JARID1d enhanced recruitment of the chromatin remodeling complex, NURF, and the basal transcription machinery near the transcriptional start site, revealing a role for JARID1d in regulation of transcriptional initiation through H3K4 demethylation.",

author = "Lee, {Min Gyu} and Jessica Norman and Ali Shilatifard and Ramin Shiekhattar",

note = "Funding Information: We thank Drs. D. Reinberg, T. Jenuwein, and H. Koga for their antibodies; Dr. D. Bochar for recombinant AOF1; and Kazusa DNA Research Institute Foundation for KIAA0234 cDNA. We extend our gratitude to Drs. D. Baillat, C. Wynder, S. McMahon, and X. Zhang for helpful advice and technical assistance; to Henry Hoff for protein expression; and to Matt Hart, Tom Beer, Kaye Speicher, and Dr. D. Speicher for help with mass spectrometry. R.S. was supported by a grant from NIH RO1CA090758. ",

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N1 - Funding Information: We thank Drs. D. Reinberg, T. Jenuwein, and H. Koga for their antibodies; Dr. D. Bochar for recombinant AOF1; and Kazusa DNA Research Institute Foundation for KIAA0234 cDNA. We extend our gratitude to Drs. D. Baillat, C. Wynder, S. McMahon, and X. Zhang for helpful advice and technical assistance; to Henry Hoff for protein expression; and to Matt Hart, Tom Beer, Kaye Speicher, and Dr. D. Speicher for help with mass spectrometry. R.S. was supported by a grant from NIH RO1CA090758.

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N2 - Histone methylation is a posttranslational modification regulating chromatin structure and gene regulation. BHC110/LSD1 was the first histone demethylase described to reverse dimethyl histone H3 lysine 4 (H3K4). Here we show that JARID1d, a JmjC-domain-containing protein, specifically demethylates trimethyl H3K4. Detailed mapping analysis revealed that besides the JmjC domain, the BRIGHT and zinc-finger-like C5HC2 domains are required for maximum catalytic activity. Importantly, isolation of native JARID1d complexes from human cells revealed the association of the demethylase with a polycomb-like protein Ring6a/MBLR. Ring6a/MBLR not only directly interacts with JARID1d but also regulates its enzymatic activity. We show that JARID1d and Ring6a occupy human Engrailed 2 gene and regulate its expression and H3K4 methylation levels. Depletion of JARID1d enhanced recruitment of the chromatin remodeling complex, NURF, and the basal transcription machinery near the transcriptional start site, revealing a role for JARID1d in regulation of transcriptional initiation through H3K4 demethylation.

AB - Histone methylation is a posttranslational modification regulating chromatin structure and gene regulation. BHC110/LSD1 was the first histone demethylase described to reverse dimethyl histone H3 lysine 4 (H3K4). Here we show that JARID1d, a JmjC-domain-containing protein, specifically demethylates trimethyl H3K4. Detailed mapping analysis revealed that besides the JmjC domain, the BRIGHT and zinc-finger-like C5HC2 domains are required for maximum catalytic activity. Importantly, isolation of native JARID1d complexes from human cells revealed the association of the demethylase with a polycomb-like protein Ring6a/MBLR. Ring6a/MBLR not only directly interacts with JARID1d but also regulates its enzymatic activity. We show that JARID1d and Ring6a occupy human Engrailed 2 gene and regulate its expression and H3K4 methylation levels. Depletion of JARID1d enhanced recruitment of the chromatin remodeling complex, NURF, and the basal transcription machinery near the transcriptional start site, revealing a role for JARID1d in regulation of transcriptional initiation through H3K4 demethylation.

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Physical and Functional Association of a Trimethyl H3K4 Demethylase and Ring6a/MBLR, a Polycomb-like Protein

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