HSA21 Single-Minded 2 (Sim2) Binding Sites Co-Localize with Super-Enhancers and Pioneer Transcription Factors in Pluripotent Mouse ES Cells.

Audrey Letourneau,Piero Carninci,Emilie Falconnet,Alexandre Fort,Michel Guipponi,Federico Santoni,Pascale Ribaux,Marco Garieri,Christelle Borel,Anne Vannier,Stylianos E Antonarakis,Gilda Cobellis,Jason Glenn Knott

doi:10.1371/journal.pone.0126475

Audrey Letourneau, Piero Carninci + Show 11 more

Open Access

https://doi.org/10.1371/journal.pone.0126475

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Abstract

The HSA21 encoded Single-minded 2 (SIM2) transcription factor has key neurological functions and is a good candidate to be involved in the cognitive impairment of Down syndrome. We aimed to explore the functional capacity of SIM2 by mapping its DNA binding sites in mouse embryonic stem cells. ChIP-sequencing revealed 1229 high-confidence SIM2-binding sites. Analysis of the SIM2 target genes confirmed the importance of SIM2 in developmental and neuronal processes and indicated that SIM2 may be a master transcription regulator. Indeed, SIM2 DNA binding sites share sequence specificity and overlapping domains of occupancy with master transcription factors such as SOX2, OCT4 (Pou5f1), NANOG or KLF4. The association between SIM2 and these pioneer factors is supported by co-immunoprecipitation of SIM2 with SOX2, OCT4, NANOG or KLF4. Furthermore, the binding of SIM2 marks a particular sub-category of enhancers known as super-enhancers. These regions are characterized by typical DNA modifications and Mediator co-occupancy (MED1 and MED12). Altogether, we provide evidence that SIM2 binds a specific set of enhancer elements thus explaining how SIM2 can regulate its gene network in neuronal features.

Highlights

Down syndrome (DS) results from trisomy of human chromosome 21 (T21)
We have shown how the identification and characterization of the Single-minded 2 (SIM2) DNA binding sites improve the understanding of its molecular function and potential role in the manifestations of DS
We have identified 1229 binding loci for SIM2 and shown that a significant fraction of target genes located in the vicinity were involved in neuronal development processes

Summary

Introduction

Down syndrome (DS) results from trisomy of human chromosome 21 (T21). It is the most frequent live-born aneuploidy, affecting 1 in 750 newborns. Identification of SIM2 DNA Binding Sites transcription factors are important candidates to explain some DS features. Transcription factors are known to play a global role in the gene transcription regulation via their direct or indirect binding to promoter and enhancer elements. Their dysregulation (in trisomic cells for instance) is likely to impact the expression of the target genes leading to the perturbation of a variety of distinct molecular pathways. Single-minded 2 (SIM2) appears to be a relevant candidate to explain some DS features, in particular the cognitive impairment

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