Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1195629 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR31643573_1.fastq.gz | Fastqsanger.gz | |||
| SRR31643573_2.fastq.gz | Fastqsanger.gz | |||
| SRR31643574_1.fastq.gz | Fastqsanger.gz | |||
| SRR31643574_2.fastq.gz | Fastqsanger.gz | |||
| SRR31643575_1.fastq.gz | Fastqsanger.gz |
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Project description:HDGF-related protein 3 (HRP3, also known as HDGFL3) belongs to the family of HDGF-related proteins (HRPs) and plays an essential role in hepatocellular carcinoma pathogenesis. All HRPs have a PWWP domain at the N-terminus that binds both histone and DNA substrates. Despite previous advances in PWWP domains, the molecular basis by which HRP3 interacts with chromatin is unclear. In this study, we solved the crystal structures of the HRP3 PWWP domain in complex with various double-stranded DNAs with/without bound histone peptides. We found that HRP3 PWWP bound to the phosphate backbone of the DNA minor groove and showed a preference for DNA molecules bearing a narrow minor groove width. In addition, HRP3 PWWP preferentially bound to histone peptides bearing the H3K36me3/2 modification. HRP3 PWWP uses two adjacent surfaces to bind both DNA and histone substrates simultaneously, enabling us to generate a model illustrating the recruitment of PWWP to H3K36me3-containing nucleosomes. Cell-based analysis indicated that both DNA and histone binding by the HRP3 PWWP domain are important for HRP3 recruitment to chromatin in vivo. Our work establishes that HRP3 PWWP is a new family of minor groove-specific DNA binding proteins, which improves our understanding of HRP3 and other PWWP domain-containing proteins.
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Project description:DNA methylation is critical for regulating gene expression, necessitating its accurate placement by enzymes such as the DNA methyltransferase DNMT3A. Dysregulating this process is known to cause aberrant development and oncogenesis, yet how DNMT3A function is shaped holistically by its three domains remains challenging to study. Through in situ mutational scanning, we found mutations in the PWWP domain, a histone reader, that modulate enzyme activity by affecting DNA binding, despite preserving histone recognition and protein stability. To investigate the consequences of these mutations on DNMT3A function in cells, we expressed ectopic Dnmt3a2 variants in embryonic stem cells and used reduced representation bisulfite sequencing and histone modification ChIP-seq to study the resulting patterns of de novo DNA methylation. Our data show that PWWP domain DNA affinity is required for full activity in cells and constitutes a noncanonical function of the PWWP domain.
2022-09-05 | GSE199890 | GEO
Project description:The TRIM-NHL protein Meiotic P26 (Mei-P26) governs gene expression and controls stem cell fate in Drosophila. Mei-P26 represses the translation of the key regulator protein Nanos and induces miRNA-dependent silencing to regulate stem cell renewal, differentiation and proliferation. The structural and mechanistic details of mRNA target recognition and RNA binding by its C-terminal NHL domain remain elusive. To identify its cellular target RNAs, we performed iCLIP2 experiments in cultured Drosophila SL2 cells that were transfected with Flag-tagged Mei-P26 full-length, or its NHL domain.
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Project description:Structural basis of H2A.Z recognition and H4K20 methylation by SUV420H2
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Project description:Recognition of modified histones by “reader” proteins plays a critical role in the regulation of transcription1. H3K36 trimethylation (H3K36me3) is deposited onto the nucleosomes in the transcribed regions following RNA polymerase II (Pol II) elongation. In yeast, this mark in turn recruits epigenetic regulators to reset the chromatin at an appropriate state to suppress cryptic transcription2,3. However, much less is known about the role of H3K36me3 in transcription regulation in mammals. This is further complicated by the transcription-coupled incorporation of the histone variant H3.3 in gene bodies4. Here we show that the candidate tumor suppressor ZMYND11 specifically recognizes H3K36me3 on H3.3 (H3.3K36me3) and regulates Pol II elongation. Structural studies reveal that in addition to the trimethyl-lysine binding by an aromatic cage within the PWWP domain, the H3.3-dependent recognition is mediated by the encapsulation of the H3.3-specific “Ser31” residue in a composite pocket formed by the tandem bromo-PWWP domains of ZMYND11. ChIP-sequencing analysis reveal a genome-wide colocalization of ZMYND11 with H3K36me3 and H3.3 in gene bodies, and its occupancy requires the pre-deposition of H3.3K36me3. Although ZMYND11 is associated with highly expressed genes, it functions as an unconventional transcription corepressor via modulating the transition of the promoter-proximal paused Pol II to elongation. ZMYND11 is critical for the repression of a transcriptional program that is essential for tumor cell growth; higher expression of ZMYND11 is observed in triple-negative breast cancer patients with better prognosis. Consistently, overexpression of ZMYND11 suppresses cancer cell growth and tumor formation in mice. Together, this study identifies ZMYND11 as an H3.3-specific reader of H3K36me3 that links the histone variant-mediated transcription elongation control to tumor suppression. ChIP-seq analysis of ZMYND11, H3K36me3 in U2OS cells and ZMYND11 knockdown cells; ChIP-seq of H3.3 in Flag-H3.3 stable U2OS cells; RNA-seq of ZNYMD11 depleted U2OS cells.
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Project description:In Drosophila the chromosomal kinase JIL-1 is responsible for most interphase histone H3S10 phosphorylation and has been proposed to protect active chromatin from acquiring heterochromatic marks, like dimethylated histone H3K9 (H3K9me2) and HP1. Here, we show that JIL-1’s targeting to chromatin depends on a PWWP domain-containing protein JASPer (JIL-1 Anchoring and Stabilizing Protein). The JASPer-JIL-1 (JJ)-complex is the major form of the kinase in vivo and is targeted to active genes and telomeric transposons via binding of the PWWP domain of JASPer to H3K36me3 nucleosomes, where the complex modulates the transcriptional output. JIL-1 and JJ-complex depletion in cycling cells lead to small changes in H3K9me2 distribution at active genes and telomeric transposons. Finally, we identify several interactors of the endogenous JJ-complex and propose that JIL-1 not only prevents heterochromatin formation but also coordinates chromatin-based regulation in the transcribed part of the genome.
2019-10-09 | PXD012790 | Pride
Project description:Precise deposition of CpG methylation is critical for mammalian development and tissue homeostasis and is often dysregulated in human diseases. The localization of de novo DNA methyltransferases 3A (DNMT3A) and 3B (DNMT3B) is facilitated by PWWP domain recognition of histone H3 lysine 36 (H3K36) methylation (Baubec et al. 2015, Weinberg et al. 2019) and is normally excluded from CpG islands (CGIs) (Wu et al. 2010). However, CpG methylation of CGIs that are regulated by Polycomb repressive complexes (PRCs) has been observed during embryogenesis (Chen et al. 2019), cellular differentiation (Mohn et al. 2008), and cancer progression (Ohm et al. 2007, Schlesinger et al. 2007, Widschwendter et al. 2007), suggesting that an uncharacterized mechanism exists to compete for de novo DNMT recruitment. Here we report that DNMT3A PWWP domain mutations recently identified in paragangliomas (Remacha et al. 2018) and microcephalic dwarfism (Heyn et al. 2019) promote localization of DNMT3A to CGIs in a PRC1-dependent manner. Genome-wide analysis shows that DNMT3A PWWP mutants redistribute to regions containing ubiquitylation of histone H2A at lysine 119 (H2AK119Ub) deposited by PRC1, irrespective of the levels of PRC2-catalyzed tri-methylation of histone H3 at lysine 27 (H3K27me3). DNMT3A, but not DNMT3B, is capable of directly interacting with H2AK119Ub-modified nucleosomes through a putative amino-terminal ubiquitin-dependent recruitment (UDR) region, which serves as an alternative form of genomic targeting in cells upon loss of PWWP reader function. Ablation of PRC1 abrogates localization of DNMT3A PWWP mutants to CGIs and prevents aberrant hypermethylation at these sites. Our study implies that a balance between DNMT3A recruitment by distinct reader domains guides de novo CpG methylation and may underlie the abnormal DNA methylation landscapes observed in human cancers and developmental disorders.
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Project description:Structural basis of nucleosomal H4K20 recognition and methylation by SUV420H1 methyltransferase
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