The Lewis Lab

🚨New preprint! We built a cell-free genomics platform (GATO-seq) to probe transcriptional regulation and discovered a “super pause” sequence that triggers a new Pol II active-site conformation. Huge shout-out to @robertovn.bsky.social for pulling off this monster of a project. tinyurl.com/superpause

Ancient co-option of LTR retrotransposons as yeast centromeres - Nature Evolutionarily related ‘proto-point’ centromeres providing resolution to the evolutionary origins of point centromeres are identified in yeast, and comparison shows they evolved in an ancestor with re...

Our paper is now out in Nature:

“Ancient co-option of LTR retrotransposons as yeast centromeres”

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

A short thread on how retrotransposons helped give rise to yeast point centromeres.

1/14

Loss of SETDB1-mediated H3K9me3 in human neural progenitor cells leads to transcriptional activation of L1 retrotransposons Abstract. Heterochromatin is characterized by an inaccessibility to the transcriptional machinery and is associated with the histone mark H3K9me3. However,

New paper from my lab out in NAR. We found that young L1 elements are controlled by SETDB1 and H3K9me3 in human neural progenitor cells via a mechanism independent of HUSH and TRIM28/KZNFs.

academic.oup.com/nar/article/...

DOT1L provides transcriptional memory through PRC1.1 antagonism - Nature Cell Biology Neville, Ferguson et al. show that non-canonical Polycomb repressive complex 1.1-mediated gene silencing is antagonized by DOT1L and is required for the therapeutic efficacy of Menin and DOT1L inhibit...

H3K79me2/3 is sufficient to antagonise PRC1 www.nature.com/articles/s41...

H4K16 acylations destabilize chromatin architecture and facilitate transcriptional response during metabolic perturbations Nitsch et al. show that short-chain acylations of histone H4K16, acetylation (C2), propionylation (C3), and butyrylation (C4) modulate chromatin structure in vitro. These effects can translate in vivo...

Now final version out: Our manuscript connecting histone modifications with metabolism: How H4K16 acylations regulate inter +intranucleosomal interactions and confer resilience to metabolic challenges in vivo. Thanks to the team+ @sandrani.bsky.social

Enjoy 👇👇 www.cell.com/molecular-ce...

Double stranded RNA sensing is silenced during early embryonic development Nature Communications - The type I interferon response is suppressed during early development, making embryos susceptible to pathogens. Here, the authors show that this suppression contributes to...

Happy to share with you our work on how the interferon response impacts embryonic development 🦠Mammalian embryos contain endogenous dsRNAs that resemble viruses and can be misrecognised by the dsRNA sensor MDA5.
Thanks to all collaborators, we could not have done it without you 🤩

rdcu.be/eWMfA

Read in Nature: nature.com/articles/s41586-025-09899-8

Stress controls epigenetic inheritance!

A histone ubiquitylation-based regulatory hub links stress/environmental signaling to heterochromatin self-propagation and epigenetic inheritance-reshaping how we think about development, drug resistance, and cancer
👉 nature.com/articles/s41586-025-09899-8

Nice structural and biochemical dissection of how ATRX engages nucleosomes and couples ATP hydrolysis to productive sliding via a distinctive mechanism. www.biorxiv.org/content/10.6...

Epimutations: raw material for evolution? - The EMBO Journal Epigenetics is fundamental to cell differentiation as it enables cells with identical genomes to adopt distinct fates. Some epigenetic information can also be transmitted between generations, in a pro...

Need a bit of escapism? Not exactly Lord of the Rings, but in similar vein:
doi.org/10.1038/s443...

Now online in Cancer Discovery @aacrjournals.bsky.social: LINE-1 Locus Transcription Nucleates Oncogenic Chromatin Architecture - by Michael Lee, Yuannyu Zhang, Jian Xu, and colleagues doi.org/10.1158/2159... @stjuderesearch.bsky.social

What in the name of S-adenosylmethionine is this.... Somewhere a DNMT is drafting a strongly worded letter to this worksheet.

Reevaluation of whether histones are asymmetrically segregated during asymmetric divisions of stem cells in Drosophila | PNAS Recent work suggests that asymmetric segregation of preexisting and newly synthesized canonical histone 3.1 (H3.1), but not variant histone 3.3A (H...

Reevaluation of whether histones are asymmetrically segregated during asymmetric divisions of stem cells in Drosophila | PNAS www.pnas.org/doi/10.1073/...

Dynamic evolution of EZHIP, an inhibitor of the Polycomb Repressive Complex 2 in mammals The Polycomb Repressive Complex 2 (PRC2) is an ancient, conserved chromatin-interacting complex that controls gene expression, facilitating differentiation and cellular identity during development. It...

@pravrutharaman.bsky.social got super intrigued about EZHIP/CATACOMB, previously identified as a histone H3K27M mimic of PRC2. You can read about her efforts here: www.biorxiv.org/content/10.6... We hope these analyses will help spur more analyses in this very cool gene! 1/

SET1/MLL complexes control transcription independently of H3K4me3 Histone H3 lysine 4 trimethylation (H3K4me3) at gene promoters is thought to play a central role in gene transcription. H3K4 methylation is deposited by the SET1 (A/B) and MLL (1-4) multi-protein comp...

An early Christmas present for those interested in chromatin and transcription! Fantastic work from @au-ho-yu.bsky.social and @aleksszczurek.bsky.social . Thanks to Inge and Michiel for their help. Please repost!

www.biorxiv.org/content/10.6...

...and the DNA becomes left-handed

Our Science paper is out!

Huge congratulations to @huabin-zhou.bsky.social, Mike Rosen, and the brilliant @janhuemar.bsky.social @juliamaristany.bsky.social and @kieran-russell.bsky.social from our group

News: bit.ly/4avnkAr and bit.ly/3XBGVHS

Great perspective by @vram142.bsky.social +K Zhang

Heterochromatin boundaries maintain centromere position, size and number - Nature Structural & Molecular Biology Carty et al. identify the H3K9 methyltransferases that restrict the size and position of the centromere protein A chromatin domain, maintaining functional centromeres.

Very proud to have our latest work now online in
@natsmb.nature.com. A wonderful team effort across the centromere community, across @jansenlab.bsky.social @naltemose.bsky.social @dfachinetti.bsky.social and Giunta labs. Happy reading! 1/4

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

Rapid compensatory evolution within a multiprotein complex preserves telomere integrity Intragenomic conflict with selfish genetic elements spurs adaptive changes in subunits of essential multiprotein complexes. Whether and how these adaptive changes disrupt interactions within such comp...

How to keep in step when your (protein) partner speeds up…

Here we investigated the adaptive remodeling of a protein-protein interaction surface essential for telomere protection.

Congrats to whole team!

www.science.org/doi/10.1126/...

Structural basis of herpesvirus helicase-primase inhibition by pritelivir and amenamevir Structural studies of HSV-1 helicase-primase revealed how pritelivir and amenamevir bind and block its helicase activity.

New work from Tahirov x Lim collaboration! @qixianghe.bsky.social from my lab contributed the cryo-EM structures for this work. We are excited to help explain how anti-HSV drugs work and to guide their future development.
www.science.org/doi/10.1126/...
@unmc.bsky.social @uwbiochem.bsky.social

1/ 🚀 AEBP2 isn’t what we thought.

You were told that AEBP2 promotes PRC2 activity on chromatin.

We found the opposite: the most prevalent AEBP2 isoform inhibits PRC2 activity.

👉 surl.li/cgwqcq

A thread 🧵

Human RPA is an essential telomerase processivity factor for maintaining telomeres Telomerase counteracts telomere shortening by repeatedly adding DNA repeats to chromosome ends. We identified the replication protein A (RPA) heterotrimer as a telomerase processivity factor critical ...

Our paper in Science is out! @souravagrawal.bsky.social, @rlynn.bsky.social, @susvirkar.bsky.social, and the rest of the team show human RPA is a telomerase processivity factor essential for telomere maintenance. This reshapes our thinking about telomerase regulation. www.science.org/doi/10.1126/...

Structural basis of T-loop–independent recognition and activation of CDKs by the CDK-activating kinase Cyclin-dependent kinases (CDKs) are prototypical regulators of the cell cycle. The CDK-activating kinase (CAK) acts as a master regulator of CDK activity by catalyzing the activating phosphorylation o...

Now out in Science! Cyclin-dependent kinases (CDKs) are key regulators of the cell cycle. In @vcushing.bsky.social's magnum opus, we use #cryoEM to figure out how the CDK-activating kinase recognises CDKs to fully activate them - a key step in cell cycle control.
www.science.org/doi/10.1126/...

ATP-dependent remodeling of chromatin condensates reveals distinct mesoscale outcomes Adenosine triphosphate (ATP)–dependent chromatin remodeling enzymes mobilize nucleosomes, but how such mobilization affects chromatin condensation is unclear. We investigate effects of two major remod...

Today I am so pleased to present our work on how chromatin remodelers affect mesoscale chromatin organization.
www.science.org/doi/10.1126/...

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

Requirements for establishment and epigenetic stability of mammalian heterochromatin Tatarakis et al. study how H3K9me3 heterochromatin is formed and inherited in mammalian cells. Using a synthetic heterochromatin assembly system and genetic screens, they uncover requirements for init...

Requirements for establishment and epigenetic stability of mammalian heterochromatin.
www.cell.com/molecular-ce...

The eukaryotic replisome intrinsically generates asymmetric daughter chromatin fibers DNA replication is molecularly asymmetric, due to distinct mechanisms for lagging and leading strand DNA synthesis. Whether chromatin assembly on newly replicated strands is also asymmetric remains un...

Some (+)ve news to lighten another heavy weekend: our latest preprint (c/o Mattiroli + Ramani labs) is up!
www.biorxiv.org/content/10.1...
A tour-de-force by 1st authors Bruna Eckhardt & @palindromephd.bsky.social, focusing on chromatin replication. RTs welcome; tweetorial in 3,2...(1/n)

Thrilled that our work is now finally out in Nature Comms!
rdcu.be/eG3vP

We reveal cryo-EM structures of the MRN complex bound to DNA & TRF2 - showing how DNA breaks are sensed and regulated at telomeres.
Fantastic work by first authors @yilanfan.bsky.social @filizkuybu.bsky.social & Hengjun!

Is enhancer-driven gene regulation all wrapped up? - Nature Reviews Genetics In this Comment, Wendy Bickmore discusses mechanistic models of how 3D genome organization facilitates communication between distant enhancers and their target promoters to regulate gene expression.

Very interesting new @wbickmor.bsky.social commentary on the mechanistic mystery that is very distal enhancer-promoter interactions www.nature.com/articles/s41...

Epigenetic relay: Polycomb-directed DNA methylation in mammalian development In mammals, repression of germline-specific gene expression is essential for preserving somatic cell identity and preventing disease. Germline gene silencing is often dependent on the presence of prom...

Very excited to share an excellent review from @teresa-urli.bsky.social, published one week before her PhD defense! We did a deep dive into the fascinating biology of the variant Polycomb complex, PRC1.6 (1/5) journals.plos.org/plosgenetics...

E. coli transcription factors regulate promoter activity by a universal, homeostatic mechanism Transcription factors (TFs) may activate or repress gene expression through an interplay of different mechanisms, including RNA polymerase (RNAP) recruitment, exclusion, and initiation. However, depen...

E. coli transcription factors regulate promoter activity by a universal, homeostatic mechanism | Science www.science.org/doi/10.1126/...