Bonnin, S. | bioRxiv Science

bioRxiv2021

Environmental enrichment induces epigenomic and genome organization changes relevant for cognitive function

In early development, the environment triggers mnemonic epigenomic programs resulting in memory and learning experiences to confer cognitive phenotypes into adulthood. To uncover how environmental stimulation impacts the epigenome and genome organization, we used the paradigm of environmental enrichment (EE) in young mice constantly receiving novel stimulation. We profiled epigenome and chromatin architecture in whole cortex and sorted neurons by deep-sequencing techniques. Specifically, we studied chromatin accessibility, gene and protein regulation, and 3D genome conformation, combined with predicted enhancer and chromatin interactions. We identified increased chromatin accessibility, transcription factor binding including CTCF-mediated insulation, differential occupancy of H3K36me3 and H3K79me2, and changes in transcriptional programs required for neuronal development. EE stimuli led to local genome re-organization by inducing increased contacts between chromosomes 7 and 17 (inter-chromosomal). Our findings support the notion that EE-induced learning and memory processes are directly associated with the epigenome and genome organization. Highlights- Environmental enrichment (EE) alters chromatin conformation, CTCF binding, and spatially 3D genome changes, thereby regulating cognitive function during the first steps of life after birth. - Transcription-associated gene body marks H3K79me2 and H3K36me3 are differently influenced by EE in cortical brain cells and binding is exacerbated upon stimulation in an age-dependent manner. - EE-induced changes of 3D genome organization increase inter-chromosomal interactions of genes associated with synaptic transmission and AMPA receptor genes on chromosomes 7 and 17.

neuroscience↗

bioRxiv2020

Coordinated post-transcriptional control of oncogene-induced senescence by UNR/CSDE1

Oncogene-induced senescence (OIS) is a form of stable cell cycle arrest elicited in cells as a response to oncogenic stimulation. OIS must be bypassed for transformation, but the mechanisms of OIS establishment and bypass remain poorly understood, especially at the post-transcriptional level. Here we show that the RNA binding protein UNR/CSDE1, previously involved in melanoma metastasis, unexpectedly enables OIS in primary mouse keratinocytes that have been challenged by over-expression of oncogenic H-Ras. Depletion of CSDE1 leads to senescence bypass, cell immortalization and tumor formation in vivo, indicating that CSDE1 behaves as a tumor suppressor. Using iCLIP-Seq, RNA-Seq and polysome profiling we have uncovered two independent molecular branches by which CSDE1 contributes to OIS. On one hand, CSDE1 enhances the senescence-associated secretory phenotype (SASP) by promoting the stability of SASP factor mRNAs. On the other hand, CSDE1 represses the synthesis of the pro-oncogenic RNA binding protein YBX1. Importantly, depletion of YBX1 from immortal keratinocytes rescues senescence and uncouples proliferation arrest from the SASP, revealing multilayered post-transcriptional mechanisms exerted by CSDE1 to control senescence. Our data uncover a novel function of CSDE1, and highlight the relevance of post-transcriptional control in the regulation of senescence.

molecular biology↗