James Walshe

How do flexible regions of histone chaperones team up to handle histones? Together with Fred Winston’s lab
@harvardmed.bsky.social, we reveal new insights in our study just out in Mol Cell. Hats off to James Warner and Vanda Lux @iocbprague.bsky.social for their key contributions! dlvr.it/TNB145

IWS1 positions downstream DNA to globally stimulate Pol II elongation - Nature Communications Although IWS1 has been implicated in transcription-coupled processes, its direct role in RNA polymerase II function remained undefined. Here, the authors demonstrate that IWS1 enhances Pol II elongati...

Also check out related work: www.nature.com/articles/s41...

🧬 Transcription elongation by RNA polymerase II relies on a web of elongation factors. Our new work shows how IWS1 acts as a modular scaffold to stabilize & stimulate elongation. Fantastic work by Della Syau! www.biorxiv.org/content/10.1...

and welcome to BlueSky @zhnbkv.bsky.social

Thanks all all authors, particularly to Aitu for bringing me onboard for a wonderful collaboration and Kristina Žumer and Patrick Cramer for helping get this over the line.

Happy reading!

Our results also indicate that IWS1 has a secondary role in H3K36me3 by sustaining proper transcription elongation and thereby supporting optimal histone methylation.

Critically, we show that this C-terminal region directly stimulates Pol II activity, identifying the molecular mechanism of IWS1’s effect on transcription.

Cryo-EM analysis reveals that IWS1, together with ELOF1, acts as a scaffold for elongation factors, binds non-template DNA, and positions DNA within the Pol II cleft via its C-terminal region.

We studied the role of IWS1 in transcription by combining in vivo multi-omics analysis and structural biology. Rapid depletion of IWS1 reduces global RNA synthesis and Pol II elongation velocity in human cells.
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IWS1 positions downstream DNA to globally stimulate Pol II elongation - Nature Communications Although IWS1 has been implicated in transcription-coupled processes, its direct role in RNA polymerase II function remained undefined. Here, the authors demonstrate that IWS1 enhances Pol II elongati...

Happy to share some work led by Aiturgan Zheenbekova and myself in the lab of @patrick-cramer.maxplanck.de at @mpi-nat.bsky.social

www.nature.com/articles/s41...

Many thanks to all co-authors, in particular co-first Moritz Ochmann, for their contributions and Patrick for the ongoing support.

Compare and contrast with the great work from the @lucas.farnunglab.com lab that shows, among many complementary findings, methylation can occur downstream as well. Likely more to come from other labs in the near future too!

Finally, continued transcription leads to complete upstream nucleosome reassembly, partial dissociation of the histone chaperone FACT and sequential methylation of both H3 tails, completing H3K36me3 deposition of an upstream nucleosome after Pol II passage.

Second, FACT mediated Pol II nucleosome passage leads to the transfer of the hexasome from downstream to upstream, repositioning the auto-inhibitory domain of SETD2, activating it for methylation.

We solved multiple cryo-EM structures to propose a 3-step model. First, binding of SETD2 to the elongation factor SPT6 tethers the catalytic SET domain in proximity to the upstream DNA.

Molecular mechanism of co-transcriptional H3K36 methylation by SETD2 Tri-methylation of histone H3 at residue lysine-36 (H3K36me3) is a hallmark of actively and recently transcribed genes and contributes to cellular memory and identity. The deposition of H3K36me3 occur...

Preprint Alert! Check out our take on the molecular basis for co-transcriptional H3K36me3 deposition by SETD2. www.biorxiv.org/content/10.1...