DOT1L is a barrier to histone acetylation during reprogramming to pluripotency

Wille, Coral K.; Zhang, Xiaoya; Haws, Spencer A.; Denu, John M.; Sridharan, Rupa

doi:10.1126/sciadv.adf3980

Cited by 4 publications

(3 citation statements)

References 86 publications

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“…Methodology for chromatin immunoprecipitation (ChIP)-qPCR was adapted from ChIP-seq procedures as previously described (56). 2×15 cm of WT E14 ESCs or KDM3A/KDM3B degron ESCs (Uninduced or +dTAG-13 for 4 hours) were used as starting material.…”

Section: Methodsmentioning

confidence: 99%

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KDM3A and KDM3B Maintain Naïve Pluripotency Through the Regulation of Alternative Splicing

Dillingham

Cormaty

Morgan

et al. 2023

Preprint

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Histone modifying enzymes play a central role in maintaining cell identity by establishing a conducive chromatin environment for lineage specific transcription factor activity. Pluripotent embryonic stem cells (ESCs) identity is characterized by lower abundance of gene repression associated histone modifications that enables rapid response to differentiation cues. The KDM3 histone demethylase family removes the repressive histone H3 lysine 9 dimethylation (H3K9me2). Here we uncover a surprising role for the KDM3 proteins in the maintenance of the pluripotent state through post-transcriptional regulation. We find through immunoaffinity purification of the KDM3A or KDM3B interactome and proximity ligation assays that KDM3A and KDM3B interact with RNA processing factors such as EFTUD2 and PRMT5. By generating double degron ESCs to degrade KDM3A and KDM3B in the rapid timescale of splicing, we find altered splicing, independent of H3K9me2 status. These splicing changes partially resemble the splicing pattern of the more blastocyst-like ground state of pluripotency and occurred in important chromatin and transcription factors such as Dnmt3b, Tbx3 and Tcf12. Our findings reveal non-canonical roles of histone modifying enzymes in splicing to regulate cell identity.

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Section: Methodsmentioning

confidence: 99%

“…ChIP-Seq analysis was performed as in as described (56). Briefly, H3K9me2 ChIP-Seq data for WT ESCs with the accession number GSE153651 (58) and GSE177058 (57) were downloaded from Gene Expression Omnibus.…”

Section: Methodsmentioning

confidence: 99%

KDM3A and KDM3B Maintain Naïve Pluripotency Through the Regulation of Alternative Splicing

Dillingham

Cormaty

Morgan

et al. 2023

Preprint

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“…DOT1L is capable of binding with other factors to form complexes known as DOT1L-containing Complexes (or DotComs) ( 83 , 84 ). Known components of these DotComs include SIRT1 ( 85 ), AF9, ENL, AF10 ( 86 ), AF17, BCOR ( 84 , 87 ) and the Wnt signalling components TRRAP, Skp1 and beta-catenin ( 83 , 88 ). DotComs are thought to facilitate gene transcription via direct recruitment of RNA polymerase II or the repression of repressive complexes containing HDACs and SUV39H1 ( 85 , 87 ).…”

Section: General Mechanismsmentioning

confidence: 99%

An emerging maestro of immune regulation: how DOT1L orchestrates the harmonies of the immune system

Kealy,

Runting,

Thiele

et al. 2024

Front. Immunol.

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The immune system comprises a complex yet tightly regulated network of cells and molecules that play a critical role in protecting the body from infection and disease. The activity and development of each immune cell is regulated in a myriad of ways including through the cytokine milieu, the availability of key receptors, via tailored intracellular signalling cascades, dedicated transcription factors and even by directly modulating gene accessibility and expression; the latter is more commonly known as epigenetic regulation. In recent years, epigenetic regulators have begun to emerge as key players involved in modulating the immune system. Among these, the lysine methyltransferase DOT1L has gained significant attention for its involvement in orchestrating immune cell formation and function. In this review we provide an overview of the role of DOT1L across the immune system and the implications of this role on health and disease. We begin by elucidating the general mechanisms of DOT1L-mediated histone methylation and its impact on gene expression within immune cells. Subsequently, we provide a detailed and comprehensive overview of recent studies that identify DOT1L as a crucial regulator of immune cell development, differentiation, and activation. Next, we discuss the potential mechanisms of DOT1L-mediated regulation of immune cell function and shed light on how DOT1L might be contributing to immune cell homeostasis and dysfunction. We then provide food for thought by highlighting some of the current obstacles and technical limitations precluding a more in-depth elucidation of DOT1L’s role. Finally, we explore the potential therapeutic implications of targeting DOT1L in the context of immune-related diseases and discuss ongoing research efforts to this end. Overall, this review consolidates the current paradigm regarding DOT1L’s role across the immune network and emphasises its critical role in governing the healthy immune system and its potential as a novel therapeutic target for immune-related diseases. A deeper understanding of DOT1L’s immunomodulatory functions could pave the way for innovative therapeutic approaches which fine-tune the immune response to enhance or restore human health.

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