The Lewis Lab

DNA methylation at retrotransposons protects the germline by preventing NRF1-mediated activation | EMBO reports imageimageIn spermatogenesis, loss of promoter DNA methylation reactivates retrotransposons in patterns shaped by chromatin modifications and the binding of DNA methylation-sensitive transcription fac...

Really beautiful work led by Jessica Leismann in Joan Barau’s lab @imbmainz.bsky.social . If you like elegant mouse genetics, the transposon arms race, and a healthy dose of epigenetics, this one’s for you. www.embopress.org/doi/full/10.... @emboreports.org

From genes to patterns: five key dynamical systems concepts to decode developmental regulatory mechanisms Summary: Dynamical systems theory provides a powerful quantitative and intuitive framework to understand developmental processes. This Primer brings key concepts of this framework to the ever-growing ...

A Summer reading recommendation: new primer in @dev-journal.bsky.social explains how dynamical systems theory unlocks the logic of developmental patterning

Everything from bistable switches & oscillators to phase portraits & more with Python code to explore

journals.biologists.com/dev/article/...

The discovery of CENP-A, the centromere-specific histone H3 variant turns 40 years!
Grant Rowley wrote a wonderful historical piece on the cell cycle control of this fascinating piece of chromatin! Check it out.
link.springer.com/article/10.1...

The 18S rRNA methyltransferase DIMT-1 regulates lifespan in the germline later in life - PubMed Specialized ribosomes help determine which proteins are synthesized, however, the influence of age on ribosome heterogeneity and whether dysregulation of this process drives organismal aging is unknow...

Excited to see our manuscript out @natcomms.nature.com pubmed.ncbi.nlm.nih.gov/40721431/. We identified that the 18S rRNA methylase DIMT-1 regulates lifespan by functioning in the germline after midlife. 1/8

Melbournevirus encodes a shorter H2B-H2A doublet histone variant that forms structurally distinct nucleosome structures Nature Communications - Melbournevirus encodes a conserved shorter H2B-H2A doublet variant. Here the authors report a cryo-EM structure of a nucleosome-like particle reconstituted with viral H4-H3...

our paper is online! rdcu.be/exXBX . Who would have thought that some #giantviruses not only have #histones, but even histone variants that make weird #nucleosomes (pdb 9CVT). Fantastic work from Ale Villalta and Chelsea Toner, with Hugo Bisio @molbiolgv.bsky.social and Chantal Abergel

Epigenetics Update - Structural mechanism of H3K27 demethylation and crosstalk with heterochromatin markers
bit.ly/44H3zCZ

Robert K. McGinty (UNC Chapel Hill) reporting in Mol Cell

#Epigenetics #DNADemethylation #Chromatin
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Discover the breakthrough at epigenometech.com

Our results support a model where SUZ12-NBD interactions with RNA act as a kinetic buffer, limiting PRC2 activity and ensuring specific targeting to CpG islands. Loss of the NBD (VEFS) disrupts this equilibrium, driving widespread, non-specific H3K27me3 deposition. 13/13

PRC2 complexes containing the SUZ12-NBD strongly bind diverse forms of nucleic acids, including structured RNA and double-stranded DNA, significantly inhibiting enzymatic activity. PRC2 lacking the NBD (VEFS) is resistant to nucleic acid-mediated inhibition. 12/13

Domain analysis identifies a discrete nucleic acid-binding domain (NBD) within SUZ12 responsible for constraining PRC2 activity. CryoEM studies showed the NBD in close proximity to nucleic acids. Loss of this region (NEC, VEFS) causes global H3K27me3 hypermethylation. 11/13

Widespread, diffuse H3K27me3 deposition induced by VEFS expression titrates canonical PRC1 away from key genomic targets. This dispersal of PRC1 disrupts Polycomb domains, resulting in transcriptional derepression and upregulation of genes normally silenced by PRC1. 10/13

Expression of the VEFS truncation globally elevates H3K27me3 independently of non-core accessory subunits. This increase occurs across multiple cell types, including both K27M-mutant DMG cells and wild-type H3 cells, highlighting intrinsic SUZ12 regulatory mechanisms. 9/13

In vitro and in vivo data confirm PRC2 subcomplexes collectively support K27M-DMG proliferation. Disrupting PRC2 recruitment (ncMUT, VEFS) dramatically reduces tumor growth, and remarkably, VEFS expression alone leads to 100% survival in orthotopic xenograft models. 8/13

EZH2 inhibition (Tazemetostat) or disruption of PRC2 subcomplexes (shSUZ12, ncMUT, VEFS) derepresses CDKN2A, causing significant growth defects. Knockout of CDKN2A rescues DMG cells from these proliferation defects, highlighting its critical role downstream of PRC2. 7/13

RNA-seq data show that disrupting PRC2 subcomplexes (ncMUT, VEFS) in DMG cells significantly derepresses genes critical for neurodevelopment. PRC2.1/2.2 complexes thus maintain silencing of developmental regulators essential for tumor cell identity. 6/13

ChIP-seq analyses reveal PRC2.1 and PRC2.2 subcomplexes act collectively to recruit PRC2 to critical genomic loci in K27M DMGs. Mutants lacking these accessory subunits (ncMUT, VEFS) show severely impaired PRC2 localization at key target genes, including CDKN2A. 5/13

To investigate PRC2 targeting, we disrupted PRC2 subcomplexes using SUZ12 mutants. VEFS truncation removes all accessory subunits, while the non-core mutant (ncMUT) selectively disrupts PRC2.1 and PRC2.2 subcomplexes, preserving core PRC2 integrity. 4/13

Recent studies show non-core (accessory) subunits are necessary for PRC2 targeting in mammalian cells. These subunits, interacting via SUZ12, guide PRC2 precisely to CpG islands, ensuring accurate H3K27me3 deposition and gene silencing. 3/13

Diffuse midline gliomas (DMGs) carrying the H3 K27M inhibitor histone exhibit global H3K27me3 reduction but retain focal enrichment at PRC2-bound CpG islands. Understanding how this residual methylation is maintained and its functional role is a critical unresolved question. 2/13

We are excited to share our new preprint demonstrating that nucleic acid interactions with SUZ12 constrain PRC2 activity, establishing a kinetic buffer essential for targeted gene silencing and revealing vulnerabilities in diffuse midline gliomas.
www.biorxiv.org/content/10.1...

Domain analysis identifies a discrete nucleic acid-binding domain (NBD) within the SUZ12 N-terminus responsible for constraining PRC2 activity. CryoEM studies previously showed the NBD in close proximity to nucleic acids. Loss of this region (NEC, VEFS) causes global H3K27me3 hypermethylation. 11/13

Widespread, diffuse H3K27me3 deposition induced by VEFS expression titrates canonical PRC1 away from key genomic targets. This dispersal of PRC1 disrupts Polycomb domains, resulting in transcriptional derepression and upregulation of genes normally silenced by PRC1. 10/13

Expression of the VEFS truncation globally elevates H3K27me3 independently of non-core accessory subunits. This substantial increase occurs across multiple cell types, including both K27M-mutant DMG cells and wild-type H3 cells, highlighting intrinsic SUZ12 regulatory mechanisms. 9/13

In vitro and in vivo data confirm PRC2 subcomplexes collectively support K27M-DMG proliferation. Disrupting PRC2 recruitment (ncMUT, VEFS) dramatically reduces tumor growth, and remarkably, VEFS expression alone leads to 100% survival in orthotopic xenograft models. 8/13

EZH2 inhibition (Tazemetostat) or disruption of PRC2 subcomplexes (shSUZ12, ncMUT, VEFS) derepresses CDKN2A, causing significant growth defects. Knockout of CDKN2A rescues DMG cells from these proliferation defects, highlighting its critical role downstream of PRC2. 7/13

RNA-seq data show that disrupting PRC2 subcomplexes (ncMUT, VEFS) in DMG cells significantly derepresses genes critical for neurodevelopment. PRC2.1/2.2 complexes thus maintain silencing of developmental regulators essential for tumor cell identity. 6/13

ChIP-seq analyses reveal PRC2.1 and PRC2.2 subcomplexes act collectively to recruit PRC2 to critical genomic loci in K27M DMGs. Mutants lacking these accessory subunits (ncMUT, VEFS) show severely impaired PRC2 localization at key target genes, including CDKN2A. 5/13

To investigate PRC2 targeting, we disrupted PRC2 subcomplexes using SUZ12 mutants. VEFS truncation removes all accessory subunits, while the non-core mutant (ncMUT) selectively disrupts PRC2.1 and PRC2.2 subcomplexes, preserving core PRC2 integrity. 4/13

Recent studies show non-core (accessory) subunits are necessary for PRC2 targeting in mammalian cells. These subunits, interacting via SUZ12, guide PRC2 precisely to CpG islands, ensuring accurate H3K27me3 deposition and gene silencing. 3/13

Diffuse midline gliomas (DMGs) carrying the H3 K27M inhibitor histone exhibit global loss of H3K27me3 but retain focal enrichment at PRC2-bound CpG islands. Understanding how this residual H3K27me3 is maintained, and its functional significance, may reveal critical therapeutic vulnerabilities. 2/13

How do chromatin remodelers use #IDRs to find TF binding partners? In our new Molecular Cell paper, we show that β-catenin is an adaptor that links SWI/SNF (cBAF) subunit ARID1A with binding partners via IDR-domain interactions.
www.cell.com/molecular-ce...