The Lewis Lab

...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/...

Figure I. Origins of transposable element (TE)-encoded and TE-derived proteins in cancer.

"Unmasked: transposable elements as drivers and targets in cancer"
by Ting Wang & colleagues

"This review synthesizes a growing body of work that positions TEs as both catalysts and antagonists of the tumor state."

Check it out!
authors.elsevier.com/sd/article/S...

Excited to share my postdoc work, out on bioRxiv today! Histones package DNA into nucleosomes to form the building blocks of chromatin, but how modular and programmable is this system? 1/9

How can we understand the earliest events in evolution of eukaryotic immunity? @yao-li.bsky.social reports incredible molecular fossils of complete bacterial-like operons in eukaryotes that illuminate how animal immunity was first acquired from anti-phage defense

www.biorxiv.org/content/10.1...

Activation of transposable elements is linked to a region- and cell-type-specific interferon response in Parkinson's disease Parkinson's disease (PD) is a common age-related neurodegenerative disorder involving a neuroinflammatory response, the cause of which remains unclear. Transposable elements (TE) have been linked to i...

New preprint from my lab! We describe how transposable elements are activated in Parkinson’s disease, which is linked to an interferon response. We believe this study significantly advances our understanding of transposons and their role in human brains.

www.biorxiv.org/content/10.1...

DNA methylation influences human centromere positioning and function - Nature Genetics Genome-wide and targeted perturbation of DNA methylation at centromeres affects CENP-A positioning and centromere structure, resulting in aneuploidy and reduced cell viability.

#1 Centromeres are epigenetic loci defined by CENP-A, positioned in unmethylated DNA flanked by highly methylated regions. Our work, published in @natgenet.nature.com in collaboration with @naltemose.bsky.social investigates the role of DNAme at human centromeres www.nature.com/articles/s41...

UCD co-lead breakthrough discovering genetic mechanism driving Weaver syndrome

Delighted that our work on EZH2 dominant negativity in Weaver syndrome is now out in Genes & Development!

This exciting work on chromatinopathies 🧬 was in collab with @adrianbracken.bsky.social and spearheaded by Orla Deevy.

@ucddublin.bsky.social @ucd-sbbs.bsky.social

www.ucd.ie/newsandopini...

New paper on the role of H3K4me3 at enhancers! We (led by Haoming Yu) used dCas9 epigenome editing to add H3K4me3 to intergenic enhancers. This was (1) sufficient to turn up transcription at open, active regions and (2) has no effect on target gene transcription. genesdev.cshlp.org/content/earl...

Ubiquitination of the histone variant mH2A1.2 prevents toxic RAD18 accumulation at a subset of genomic loci upon replication stress Using biochemical assays and a mutant disrupting RNF168-dependent ubiquitination of the histone variant macroH2A1.2, Galloy et al. identified an unexpected role for histone mH2A1.2 ubiquitination in p...

I am very excited to share the newest paper of the lab, a huge amount of work led by our talented PhD student Maxime Galloy, in close collaboration with Andréanne Blondeau, our dedicated research assistant for 10 years! 🙌

www.cell.com/molecular-ce...

I am thrilled to share with you my first co-corresponding author Nature paper with Jos Jonkers. This project was led by the extraordinary @sarahmoser.bsky.social . Congratulations, and thank you to all the authors, @nkinl.bsky.social , and @oncodeinstitute.bsky.social for their support.

The chemotherapy-induced senescence-associated secretome promotes cell detachment and metastatic dissemination through metabolic reprogramming Cellular senescence, characterized by a stable cell cycle arrest, is a well-documented consequence of several widely used chemotherapeutics that has context-dependent roles in cancer. Although senesce...

The summer has been busy! Along with the move and a PhD defense, we have updated two preprints:
www.biorxiv.org/content/10.1...

www.biorxiv.org/content/10.1...

What better way to launch our new account with the publication of @jmstein.bsky.social latest paper from the lab! 🧪 Check out the 🧵 below to learn more about tkPAINT and how we use it to image proteins, DNA, and RNA in the nucleus using DNA-PAINT.

The molecular basis of lamin-specific chromatin interactions - Nature Structural & Molecular Biology Wang, Kronenberg-Tenga, Rosti and colleagues use several structural approaches to analyze the distribution of nucleosomes at the lamin–chromatin interface, test the impact of lamins on nucleosome dens...

Epigenetics Update - The molecular basis of lamin-specific chromatin interactions go.nature.com/3GRXydB

Chiara Lanzuolo (INGM) and Ohad Medalia (University of Zurich) reporting in NSMB

#Epigenetics #Chromatin #Lamin
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Gain deeper insights into gene regulation; epigenometech.com

A novel deep learning-based framework reveals a continuum of chromatin sensitivities across transcription factors The genome-wide binding of many transcription factors (TFs) depends not only on the presence of their recognition motifs, but also on the surrounding chromatin context. This raises the question of how...

Excited to share our latest preprint. www.biorxiv.org/content/10.1.... Lead by Lukas, we investigated multiple ways of assessing a TF's sensitivity to chromatin based on genome-wide binding profiles. The developed methods allowed us to quantify chromatin sensitivity across tested TFs.

By contrast, removing the SUZ12 NBD yields an RNA-poor PRC2 that spreads H3K27me3 broadly in the genome, creating a massive low-level methylation background that decoys PRC1 away from its canonical targets- a global shift in mark abundance that doesn’t happen in the BRG1 setting.