Chromodomain Protein CDYL Acts as a Crotonyl-CoA Hydratase to Regulate Histone Crotonylation and Spermatogenesis

Lysine crotonylation is a newly discovered post‐translational modification, which is structurally and functionally different from the widely studied lysine acetylation. Recent advances in the identification and quantification of lysine crotonylation by mass spectrometry have revealed that non‐histone proteins are frequently crotonylated, implicating it in many biological processes through the regulation of chromatin remodelling, metabolism, cell cycle and cellular organization. In this review, we summarize the writers, erasers and readers of lysine crotonylation, and their physiological functions, including gene transcription, acute kidney injury, spermatogenesis, depression, telomere maintenance, HIV latency and cancer process. These findings not only point to the new functions for lysine crotonylation, but also highlight the mechanisms by which crotonylation regulates various cellular processes.

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“…Genome-wide removal of histones from chromatin and their replacement is a unique epigenetic event during spermatogenesis. 40 Liu et al 41…”

Section: Regulation Of Spermatogenesismentioning

confidence: 99%

Functions and mechanisms of lysine crotonylation

Wan

Chu

et al. 2019

J Cellular Molecular Medi

103

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“…However, over the process of evolution, non-simian mammals have been shown to lack the Y-linked CDY genes 2 . Nevertheless, in mice, a short transcript of CDYL1 displays testis-specific expression 1,2 , and the normal expression of mouse CDYL1 is essential for spermatogenesis and male fertility, similar to human CDY1/2 genes 6,13 . Both human and mouse CDYL1 function as transcriptional corepressors 14,15 .…”

Section: Introductionmentioning

confidence: 99%

“…The chromodomains of the CDY family are highly homologous to chromodomains in HP1 and Polycomb, and as such, they also recognize the lysine-methylated ARKS motif embedded in histone and non-histone proteins 4,5 . The catalytic domain of mouse CDYL1 has been reported to exhibit crotonyl-CoA hydratase activity 6 .…”

Section: Introductionmentioning

confidence: 99%

“…Both human and mouse CDYL1 function as transcriptional corepressors 14,15 . This CDYL1-mediated repressive function has recently been linked to its role in converting crotonyl-CoA, an active mark in transcription, to β-hydroxybutyryl-CoA 6 , and this crotonyl-CoA hydratase activity contributes to its role in spermatogenesis 6 . However, in another mouse study, conditional knockout of CDYL1 does not affect global histone crotonylation, but causes disordered patterns of histone methylation and acetylation in testis 13 .…”

Section: Introductionmentioning

confidence: 99%

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Structural basis for the binding selectivity of human CDY chromodomains

Cheng

Lyu

et al. 2019

Preprint

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The CDY (Chromodomain on the Y) family is a small family of chromodomain containing proteins, whose chromodomains closely resemble those in HP1 and Polycomb. The CDY proteins play an essential role in normal spermatogenesis and brain development. Dysregulation of their expression has been linked to male infertility and various neurological diseases. Like the chromodomains of HP1 and Polycomb, the CDY chromodomains also recognize the lysinemethylated ARKS motif embedded in histone and non-histone proteins. Interestingly, the CDY chromodomains exhibit different binding preferences for the lysine-methylated ARKS motif in different sequence contexts. Here, we present the structural basis for selective binding of CDY1 to H3K9me3 and preferential binding of CDYL2 to H3tK27me3 over H3K27me3. Based on our structural, binding and mutagenesis data, we synthesized a more CDYL1/2 selective peptidic ligand UNC4850. Our work provides critical implications that CDYL1b's role in the regulation of neural development is dependent on its recognition of lysine-methylated ARKS motifs. morphology by repressing BDNF, a key regulator in dendrite development 16 ; it modulates neuronal intrinsic plasticity by repressing SCN8A, a sodium channel gene whose mutations cause epileptic encephalopathies 17 ; it controls neuronal migration by repressing RhoA, a gene involved in actin cytoskeleton regulation, and its deficiency causes neuronal migration disorders and increased susceptibility to epilepsy 18 ; and it contributes to stress-induced depression by repressing VGF (or VGF nerve growth factor inducible), a gene that plays a key role in synaptic plasticity 19 . CDYL1 represses expression of its target genes through recruitment of PRC2mediated H3K27me3 activity 16,17,19 , and possibly also through its own histone crotonylation ability 19 . In addition to recruiting PRC2 and its associated H3K27me3 activity, CDYL1 also recruits G9a, a histone H3K9 dimethyltransferase, which together with REST represses transcription of potential tumor suppressor genes 15 . Not surprisingly, both CDYL and G9a are upregulated in hepatocellular carcinoma (HCC), but not in non-cancerous liver tissues 20 . CDYL1 also associates with chromatin assembly factor 1 (CAF1) and the MCM complex, and recruits histone H3K9/27 methyltransferases G9a, SETDB1, and PRC2 to the replication forks for transmission of repressive chromatin marks during DNA replication 21 , or to DNA double-strand break (DSB) sites for transcriptional silencing and promotion of homology-directed DNA repair (HDR) 22 .The chromodomains of the CDY family bind to the lysine-methylated ARKS motif present in histones H3K9, H3K27 and H1.4K26 sites and in histone di-methyltransferase G9a in vitro 4,5 .Since CDYL1 has been shown to be associated with the lysine methyltransferases G9a, SETDB1 and PRC2, which are also able to methylate the lysine residue in the ARKS motif, it was proposed that CDYL1 and lysine methyltransferases, such as G9a and PRC2, synergize to propagate/transmit the H3K9me2 and H3K27me3 m...

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“…The human CDYL protein has been found to associate with histone remodeling complexes to promote heterochromatin formation and maintenance, including interactions with the Polycomb Repressive Complex 2 (PRC2) and chromatin assembly factor-1 (CAF-1) (Liu et al, 2017b;Zhang et al, 2011). CDYL specifically associates with H3K9me3 as well as di-and tri-methylated H3K27 and negatively regulates lysine crotonylation, a modification associated with active promoters (Franz et al, 2009;Liu et al, 2017a;Zhang et al, 2011). CDYL is also a component of the Repressor element-1 silencing transcription factor (REST) complex.…”

Section: Introductionmentioning

confidence: 99%

ADrosophilaInsulator Interacting Protein Suppresses Enhancer-Blocking Function and Modulates Replication Timing

et al. 2019

Preprint

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Insulators play important roles in genome structure and function in Drosophila and mammals.More than six different insulator proteins are required in Drosophila for normal genome function, whereas CTCF is the only identified protein contributing to insulator function in mammals.Interactions between a DNA binding insulator protein and its interacting partner proteins define the properties of each insulator site. The different roles of insulator protein partners in the Drosophila genome and how they confer functional specificity remain poorly understood.Functional analysis of insulator partner proteins in Drosophila is necessary to understand how genomes are compartmentalized and the roles that different insulators play in genome function. In Drosophila, the Suppressor of Hairy wing [Su(Hw)] insulator is targeted to the nuclear lamina, preferentially localizes at euchromatin/heterochromatin boundaries, and is associated with the Gypsy retrotransposon. The properties that the insulator confers to these sites rely on the ability of the Su(Hw) protein to bind the DNA at specific sites and interact with Mod(mdg4)-67.2 and CP190 partner proteins. HP1 and insulator partner protein 1 (HIPP1) is a recently identified partner of Su(Hw), but how HIPP1 contributes to the function of Su(Hw) insulators has not yet been elucidated. Here, we find that mutations in the HIPP1 crotonase-like domain have no impact on the function of Su(Hw) enhancer-blocking activity but do exhibit an impaired ability to repair double-strand breaks. Additionally, we find that the overexpression of each HIPP1 and Su(Hw) causes defects in cell proliferation by limiting the progression of DNA replication. We also find that HIPP1 overexpression suppresses the Su(Hw) insulator enhancer-blocking function.

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Chromodomain Protein CDYL Acts as a Crotonyl-CoA Hydratase to Regulate Histone Crotonylation and Spermatogenesis

Cited by 195 publications

References 43 publications

Functions and mechanisms of lysine crotonylation

Functions and mechanisms of lysine crotonylation

Structural basis for the binding selectivity of human CDY chromodomains

ADrosophilaInsulator Interacting Protein Suppresses Enhancer-Blocking Function and Modulates Replication Timing

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