Global stabilization of the transcriptome in mitotic cells - The EMBO Journal In the presence of cell division errors, mammalian cells can pause in mitosis for tens of hours with little to no transcription, while still requiring continued translation for viability. These unique aspects of mitosis require substantial adaptations to gene expression. During interphase, homeostatic control of mRNA levels involves a constant balance of transcription and degradation, with a median mRNA half-life of ~2–4 h. If such short half-lives persisted in mitosis, cells would be expected to rapidly deplete their transcriptome without new transcription. Here, we report that the transcriptome is globally stabilized during prolonged mitotic delays. Median mRNA half-lives are increased >4-fold during mitotic arrest compared to interphase, buffering mRNA levels in the absence of new synthesis. Moreover, poly(A) tail-length profiles change during mitotic arrest, strongly suggesting a partial mitotic repression of deadenylation. In contrast, siRNA-directed mRNA degradation machinery remains active. We further show that mitotic mRNA stabilization depends on PABPC1&4. Depletion of PABPC1&4 during mitotic arrest reduces mRNA stability and disrupts the cells’ ability to maintain arrest, highlighting the critical physiological role of mitotic transcriptome buffering.

How can cells maintain gene expression despite minimal transcription during prolonged mitotic arrest?
@iaincheeseman.bsky.social @jimmy-ly.bsky.social et al reveal global transcriptome stabilization in mitotic cells, partly because of reduced mRNA deadenylation
link.springer.com/article/10.1...

I am excited to share our review on the mechanistic basis and functional consequences of cell cycle-specific mRNA decay and translational control. Fun work with Cheese lab's (@iaincheeseman.bsky.social) grad students Katya Khalizeva and Yi Fei Tao!
rnajournal.cshlp.org/content/earl...

First preprint of the year! New work from @jimmy-ly.bsky.social revealing unexpected roles for 5' UTR length in controlling alternate translational isoforms - important implications for both physiological cell function and rare disease. Small changes -> big impacts.

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

Scientists and clinicians convene to bridge gaps in rare disease research and care | Whitehead Institute Rare disease treatment and care relies on the combined efforts of clinicians, researchers, and families. Yet these people rarely find themselves in the same room. BridgeRD brought together stakeholder...

Rare disease treatment relies on the combined efforts of clinicians, researchers, and families. Yet these people rarely find themselves in the same room. BridgeRD brought them together last week to address the challenges of understanding, diagnosing, and treating rare diseases.

🔗 shorturl.at/pJXcu

Alternate proteins from the same gene contribute differently to health and rare disease | Whitehead Institute Iain Cheeseman and colleagues reveal the underappreciated role of single genes producing multiple proteins in atypical presentations of rare disease, and present case studies of affected patients thro...

From an accidental discovery of hidden biology to a new framework to understanding and diagnosing rare disease. Thrilled to share the most recent work from our lab and the amazing Jimmy Ly.

wi.mit.edu/news/alterna...

mRNA poly(A)-tail length is a battleground for coronavirus–host competition Most eukaryotic mRNAs contain a poly(A) tail, which in post-embryonic cells enhances their stability. Many cytoplasmic RNA viruses also harbor poly(A) tails on their genomic RNA and mRNAs. Here, we re...

Check out the latest work from our lab, led by Arash Latifkar @ara-latifkar.bsky.social , www.biorxiv.org/content/10.1...

Lysosomal RNA profiling reveals targeting of specific types of RNAs for degradation Autophagy targets a wide variety of substrates for degradation within lysosomes. While lysosomes are known to possess RNase activity, the role of lysosomal RNA degradation in post-transcriptional gene...

I am excited to share my graduate work in the Sabatini and @bartellab.bsky.social labs. Since their discovery, we have known lysosomes possess RNase activity; however, their substrates were not known. Surprisingly we find specific RNAs are targeted for degradation! www.biorxiv.org/content/10.1...

Congratulations to @jimmy-ly.bsky.social on this well-deserved recognition!

His research looking at variants of known proteins offers new insight into rare genetic disorders.
tinyurl.com/5xfc3feh

Honoured to receive the IMP Birnstiel Award this year! So grateful to my mentor @iaincheeseman.bsky.social for all of his help and encouragement!! Very thankful to the @whiteheadinstitute.bsky.social community and the wonderful collaborations within the institute—especially @bartellab.bsky.social 😊🥳

The dynamics of centromere assembly and disassembly during quiescence Quiescence is a state in which cells undergo a prolonged proliferative arrest while maintaining their capacity to reenter the cell cycle. Here, we analyze entry and exit from quiescence, focusing on h...

New preprint! Graduate student Océane Marescal leverages quiescence - proliferative hibernation - to reveal unexpected dynamics for “constitutively”-localized centromere proteins. To understand the logic of cell division, you need to consider non-dividing cells.

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

Thank you Thy!!!

Thank you Andy!!!

I am incredibly grateful and honored to be recognized with the Keith Porter Prize 🥹🥳 — thank you, @ascbiology.bsky.social and @iaincheeseman.bsky.social for being the best mentor!! Congratulations to the other awardees and I am looking forward to meeting everyone in Philly

Thank you Kara!!! 🥹🥹

PAL-AI reveals genetic determinants that control poly(A)-tail length during oocyte maturation, with relevance to human fertility - Nature Communications Gene regulation in oocytes relies heavily on poly(A) tail-length changes. Here, the authors develop PAL-AI, a neural network model that predicts tail-length changes, identifies regulatory motifs, and ...

Check out the latest study from our lab, led by Coffee Xiang (@coffeebond007.bsky.social) www.nature.com/articles/s41... (1/2)

Global inhibition of deadenylation stabilizes the transcriptome in mitotic cells In the presence of cell division errors, mammalian cells can pause in mitosis for tens of hours with little to no transcription, while still requiring continued translation for viability. These unique...

Beautiful work by Katya Khalizeva from @iaincheeseman.bsky.social lab, uncovering a surprising feedback loop to globally suppress mRNA decay during mitosis! This helps explain how cells maintain their transcriptome during a mitotic arrest without new transcription!
www.biorxiv.org/content/10.1...

Global inhibition of deadenylation stabilizes the transcriptome in mitotic cells In the presence of cell division errors, mammalian cells can pause in mitosis for tens of hours with little to no transcription, while still requiring continued translation for viability. These unique...

New preprint! We solve a mystery you didn't know existed. Mitotic cells lack new transcription but require ongoing translation. Interphase mRNA half life is only 2-4 hrs. So how do cells arrest in mitosis for hours without depleting their transcriptomes?

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

Optical Pooled Screening has transformed large-scale cell biology, but lacks robust end-to-end computational strategies to process these Tb-sized datasets. New from Di Bernardo et al (@mat10d.bsky.social‬):

Brieflow. A game changer for OPS + new biological insights

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

Thank you Peter !! 🎉

Thank you Seychelle!!

New preprint drop! Check out work from @jimmy-ly.bsky.social et al for how protein isoforms generated by alternate translation initiation create dual localization, contribute to mitochondrial function, and are mutated in disease. "Blue-tutorial" thread below.

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

Alternative start codon selection shapes mitochondrial function during evolution, homeostasis, and disease Mitochondrial endosymbiosis was a pivotal event in eukaryotic evolution, requiring core proteins to adapt to function both within the mitochondria and in the host cell. Here, we systematically profile...

Excited to share my work with @iaincheeseman.bsky.social! We show that alternative translation produces differentially localized protein variants mutated in rare human diseases. This was a fun collaboration, blending cell biology with evolution and clinical genetics!

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

Countdown to an epic new pre-print.

Mitochondria are cells within our cells. They need the same core activities - replication, transcription, translation. How do cells enable these diverse activities in both compartments? We uncover an unexpected + broad strategy with ancient origins. Stay tuned!