LSD2/KDM1B and Its Cofactor NPAC/GLYR1 Endow a Structural and Molecular Model for Regulation of H3K4 Demethylation

Fang, Rui; Chen, Fei Xavier; Dong, Zhenghong; Hu, Di; Barbera, Andrew J.; Clark, Erin; Fang, Jian; Yang, Ying; Mei, Pinchao; Rutenberg, M.S.; Li, Ze; Zhang, Ying; Xu, Youwei; Yang, Huirong; Wang, Ping; Simon, Matthew D.; Zhou, Qiongjie; Li, Jing; Marynick, Mark P.; Li, Xiaotian; Lu, Haojie; Kaiser, Ursula B.; Kingston, Robert E.; Xu, Yanhui; Shi, Yujiang Geno

doi:10.1016/j.molcel.2012.11.019

Cited by 87 publications

(95 citation statements)

References 48 publications

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“…The methyltransferase writer ASH2L and the demethylase erasers PHF8, KDM5A, and KDM5B were especially enriched in the H3K4me3 preparation, consistent with their functions in promoter regions (20)(21)(22). The PWWP domain reader N-PAC, an LSD2/KDM1B cofactor that stimulates H3K4 demethylation, was especially enriched in the H3K36me3 preparation (23). The chromobox readers CBX1, CBX3, and CBX5 and the histone methyltransferase writer SETDB1 were especially enriched in the H3K9me3 and H4K20me3 preparations, consistent with their functions in heterochromatic regions (24).…”

Section: Significancementioning

confidence: 57%

Chromatin proteomic profiling reveals novel proteins associated with histone-marked genomic regions

Xiong

Dadon

Abraham

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

128

112

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More than a thousand proteins are thought to contribute to mammalian chromatin and its regulation, but our understanding of the genomic occupancy and function of most of these proteins is limited. Here we describe an approach, which we call "chromatin proteomic profiling," to identify proteins associated with genomic regions marked by specifically modified histones. We used ChIP-MS to identify proteins associated with genomic regions marked by histones modified at specific lysine residues, including H3K27ac, H3K4me3, H3K79me2, H3K36me3, H3K9me3, and H4K20me3, in ES cells. We identified 332 known and 114 novel proteins associated with these histone-marked genomic segments. Many of the novel candidates have been implicated in various diseases, and their chromatin association may provide clues to disease mechanisms. More than 100 histone modifications have been described, so similar chromatin proteomic profiling studies should prove to be valuable for identifying many additional chromatin-associated proteins in a broad spectrum of cell types.chromatin | genomics | proteomics T here are more than 1,000 transcription factors, cofactors, and chromatin regulators encoded in the mammalian genome, but we have limited understanding of the genomic occupancy and function of most of these (1-4). Understanding how these proteins interact with specific active and repressed portions of the genome would provide clues to their functions in global gene control, but limitations inherent in widely used genomic and proteomic technologies make acquiring this information laborious and expensive. Chromatin immunoprecipitation coupled to sequencing (ChIP-seq) can reveal the sites that a specific protein occupies in the genome (5-7) but is laborious and is limited by the availability of antibodies specific to candidate genome-binding proteins. Mass spectrometry (MS) can identify large populations of proteins present in specific preparations (8-10) but does not reveal how these proteins occupy specific portions of the genome. A recently developed approach combined ChIP with MS (ChIP-MS) to identify protein complexes that are associated with other proteins known to occupy sites in the genome (11-13). Here we adapt this approach to profile the proteins associated with chromatin containing specific histone modifications across the genome of mouse embryonic stem cells (mESCs). These chromatin modifications mark regions of the genome where specific transcriptional activities occur, thus implicating the associated proteins in these activities.

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Section: Significancementioning

confidence: 57%

Chromatin proteomic profiling reveals novel proteins associated with histone-marked genomic regions

Xiong

Dadon

Abraham

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

128

112

View full text Add to dashboard Cite

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“…6C). Furthermore, the aromatic cage in the LSD2 CW domain is filled with the side chain of residues Leu-340 and Ile-343 in the adjacent SWIRM domain (30). These observations may explain why LSD2 does not bind the H3 peptide (13).…”

Section: Structural Comparison With Other Cw Domains Explains Why Sommentioning

confidence: 99%

“…Structural Basis for Selective Binding of H3K4me3 by ZCWPW2 and MORC3-There are only three CW domain structures available in databases: the NMR structure of ZCWPW1-CW in complex with H3K4me3 (8), the NMR structure of AtASHH2-CW in free state (9), and crystal structures of full-length LSD2 including the CW domain (13,30). To extend our understanding of the molecular mechanism of selective binding of H3K4me3 by the CW family, we solved the crystal structures of ZCWPW2 and MORC3 CW domains in complex with a H3(1-15) K4me3 peptide at 1.78 and 1.75 Å resolution, respectively (Table 1 and Fig.…”

Section: Zcwpw2 Morc3 and Morc4 Are Histone H3k4me3mentioning

confidence: 99%

Family-wide Characterization of Histone Binding Abilities of Human CW Domain-containing Proteins

Liu

Tempel

Zhang

et al. 2016

Journal of Biological Chemistry

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Covalent modifications of histone N-terminal tails play a critical role in regulating chromatin structure and controlling gene expression. These modifications are controlled by histone-modifying enzymes and read out by histone-binding proteins. Numerous proteins have been identified as histone modification readers. Here we report the family-wide characterization of histone binding abilities of human CW domain-containing proteins. We demonstrate that the CW domains in ZCWPW2 and MORC3/4 selectively recognize histone H3 trimethylated at Lys-4, similar to ZCWPW1 reported previously, while the MORC1/2 and LSD2 lack histone H3 Lys-4 binding ability. Our crystal structures of the CW domains of ZCWPW2 and MORC3 in complex with the histone H3 trimethylated at Lys-4 peptide reveal the molecular basis of this interaction. In each complex, two tryptophan residues in the CW domain form the "floor" and "right wall," respectively, of the methyllysine recognition cage. Our mutation results based on ZCWPW2 reveal that the right wall tryptophan residue is essential for binding, and the floor tryptophan residue enhances binding affinity. Our structural and mutational analysis highlights the conserved roles of the cage residues of CW domain across the histone methyllysine binders but also suggests why some CW domains lack histone binding ability.Chromatin structure is dynamically regulated by histone post-translational modifications, such as methylation, acetylation, phosphorylation, ubiquitination, and sumoylation (1). These post-translational modifications constitute the "histone code," which is written or erased by histone-modifying enzymes and recognized by histone code "reader" proteins (2-4).Histone methylation, such as lysine methylation at the ⑀-amino group at levels from mono-to trimethylation (me1-me3), has received extensive attention (5). A number of domains bind methylated histone tails. Prominent examples include the chromodomain, Tudor domain, MBT domain, PWWP domain, and PHD domain (4, 6, 7). The CW domain has recently been identified as a new member of the lysine methylation reader family (8 -11).The CW domain is a zinc binding domain, composed of ϳ50 amino acid residues with four conserved cysteine (C) and two conserved tryptophan (W) residues, and its name was derived from these conserved residues. CW domains are found in chromatin-associated proteins in animals and plants and grouped into 12 families based on sequence similarity (12). There are seven CW domain-containing proteins in humans, namely ZCWPW1, ZCWPW2, MORC1, MORC2, MORC3, MORC4, and LSD2 (Fig. 1A). Prior studies have shown that the CW domains of ZCWPW1 (8), MORC3 (10), and MORC4 (9) are readers of H3K4 3 methylated histones with differing preferences for histone H3K4 methylation states (i.e. ZCWPW1 and MORC3 preferentially recognize histone H3K4me3 (8, 10), whereas the CW domain of human MORC4 prefers dimethylated H3K4 (9)). The LSD2 CW domain is required for the demethylation function of LSD2 but does not bind to any H3K4 peptides (13). However, th...

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“…In contrast, KDM1B hyperDMRs and hypoDMRs showed no relationship with expression of the associated gene. This suggests that KDM1A and KDM1B play distinct roles within the oocyte: KDM1A may act a transcription factor, and misregulated methylation in the KDM1A knockout is a consequence of misregulated expression, while KDM1B demethylates K4me2 as part of the elongating RNA polymerase II (Pol II) complex (Fang et al 2010(Fang et al , 2013, and therefore the KDM1B knockout shows severe hypomethylation but normal gene expression.…”

Section: Growing Oocytes Show Global H3k36me3 Enrichment and Targetedmentioning

confidence: 99%

Dynamic changes in histone modifications precede de novo DNA methylation in oocytes

et al. 2015

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Erasure and subsequent reinstatement of DNA methylation in the germline, especially at imprinted CpG islands (CGIs), is crucial to embryogenesis in mammals. The mechanisms underlying DNA methylation establishment remain poorly understood, but a number of post-translational modifications of histones are implicated in antagonizing or recruiting the de novo DNA methylation complex. In mouse oogenesis, DNA methylation establishment occurs on a largely unmethylated genome and in nondividing cells, making it a highly informative model for examining how histone modifications can shape the DNA methylome. Using a chromatin immunoprecipitation (ChIP) and genome-wide sequencing (ChIP-seq) protocol optimized for low cell numbers and novel techniques for isolating primary and growing oocytes, profiles were generated for histone modifications implicated in promoting or inhibiting DNA methylation. CGIs destined for DNA methylation show reduced protective H3K4 dimethylation (H3K4me2) and trimethylation (H3K4me3) in both primary and growing oocytes, while permissive H3K36me3 increases specifically at these CGIs in growing oocytes. Methylome profiling of oocytes deficient in H3K4 demethylase KDM1A or KDM1B indicated that removal of H3K4 methylation is necessary for proper methylation establishment at CGIs. This work represents the first systematic study performing ChIP-seq in oocytes and shows that histone remodeling in the mammalian oocyte helps direct de novo DNA methylation events.

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LSD2/KDM1B and Its Cofactor NPAC/GLYR1 Endow a Structural and Molecular Model for Regulation of H3K4 Demethylation

Cited by 87 publications

References 48 publications

Chromatin proteomic profiling reveals novel proteins associated with histone-marked genomic regions

Chromatin proteomic profiling reveals novel proteins associated with histone-marked genomic regions

Family-wide Characterization of Histone Binding Abilities of Human CW Domain-containing Proteins

Dynamic changes in histone modifications precede de novo DNA methylation in oocytes

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