Biology subjects

Pradeepa, M. M.

Publications and source records attributed to Pradeepa, M. M..

3 recordsLinked to original sources

bioRxiv2025

Non-canonical enhancers control gene expression and cell fate in human pluripotent stem cells

Enhancers are key gene regulatory elements that ensure the precise spatiotemporal execution of developmental gene expression programmes. However recent findings indicate that approaches to identify enhancers may not capture the full repertoire of active enhancers in mammalian genomes. Here, we combine massively parallel enhancer assays with chromatin structure and transcriptome profiling to functionally annotate enhancers genome-wide in human induced pluripotent stem cells. We find that a substantial fraction ([~]40%) of accessible chromatin regions with enhancer function lack key features associated with active enhancers, including the active enhancer mark histone H3 lysine 27 acetylation and enhancer-associated RNAs. Perturbation of this class of non-canonical enhancers by CRISPR-mediated epigenome editing results in decreased levels of target gene expression and, in one instance, loss of pluripotent stem cell characteristics. Collectively, our data demonstrate enhancer activity for a class of gene regulatory elements that had until now only been associated with a neutral or inactive status, challenging current models of enhancer function.

genomics↗

bioRxiv2022

H4K16ac activates transcription of transposable elements and contribute to their cis regulatory function

Mammalian genomes harbour a large number of transposable elements (TEs) and their remnants. Many epigenetic repression mechanisms are known to silence TE transcription. However, TEs are upregulated during early development, neuronal lineage, and cancers, although the epigenetic factors contributing to the transcription of TEs have yet to be fully elucidated. Here we demonstrated that the male-specific lethal (MSL) complex mediated acetylation of histone H4 lysine 16 (H4K16ac) activates transcription of long interspersed nuclear elements (LINE1, L1) and long terminal repeats (LTRs). Furthermore, we show that the H4K16ac marked L1 and LTR subfamilies function as enhancers and are enriched with chromatin features associated with active enhancers and looping factors. L1 and LTRs enriched with histone acetylations are bound by chromatin looping factors and these regions loop with genes. CRISPR-based epigenetic perturbation and genetic deletion of L1s reveal that H4K16ac marked L1s and LTRs regulate the expression of genes in cis. Overall, TEs enriched with H4K16ac contribute to the cis-regulatory landscape of a significant portion of the mammalian genome by maintaining an active chromatin landscape at TEs. One Sentence SummaryH4K16ac activates LINE1 and ERV/LTR transcription and rewires the cis-regulatory landscape of a significant portion of the mammalian genome by increasing the transcriptional activity at TEs.

genomics↗

bioRxiv2019

Cornelia-de-Lange syndrome-associated mutations cause a DNA damage signalling and repair defect

Cornelia de Lange Syndrome is a multisystem developmental disorder typically caused by mutations in the gene encoding the cohesin loader NIPBL. The associated phenotype is generally assumed to be the consequence of aberrant transcriptional regulation. Recently, we identified a residue substitution in BRD4 associated with a Cornelia de Lange-like syndrome, that reduces BRD4 binding to acetylated histones. Here we show that, although this mutation reduces BRD4-occupancy at enhancers in mouse embryonic stem cells, it does not affect transcription. Rather it delays the cell cycle, increases DNA damage signalling, and perturbs regulation of DNA repair in mutant cells. This uncovers a new role for BRD4 in DNA repair pathway choice. Furthermore, we find evidence of a similar increase in DNA damage signalling in cells derived from NIPBL-deficient individuals, suggesting that defective DNA damage signalling and repair is also a feature of typical Cornelia de Lange Syndrome.

cell biology↗