ADNP Controls Gene Expression Through Local Chromatin Architecture by Association With BRG1 and CHD4.

Xiaoyun Sun,Yuhua Sun,Wenjun Yu,Li Li

doi:10.3389/fcell.2020.00553

Abstract

ADNP (Activity Dependent Neuroprotective Protein) is proposed as a neuroprotective protein whose aberrant expression has been frequently linked to rare neural developmental disorders and cancers, including the recently described neurodevelopmental Helsmoortel-Van der Aa syndrome. Recent studies have suggested that ADNP functions as an important chromatin regulator. However, how ADNP-regulated chromatin mechanisms control gene expression and stem cell fate commitment remains unclear. Here we show that ADNP interacts with two chromatin remodelers, BRG1 and CHD4. ADNP is required for proper establishment of chromatin accessibility, nucleosome configuration, and bivalent histone modifications of developmental genes. Loss of ADNP leads to enhancer over-activation and increased ratio of H3K4me3/H3K27me3 at key primitive endoderm (PrE) gene promoters, resulting in prominent up-regulation of these genes and priming ES cell differentiation toward endodermal cell types. Thus, our work revealed a key role of ADNP in the establishment of local chromatin landscape and structure of developmental genes by association with BRG1 and CHD4. These findings provide further insights into the role of ADNP in the pathology of the Helsmoortel-Van der Aa syndrome.

Highlights

Embryonic stem cells (ESCs) possess an epigenome and chromatin structures that are required for the maintenance of self-renewal and pluripotency
We show that ADNP functions as a key chromatin regulator- this is potentially linked to its interaction with the chromatin remodelers, BRG1 and CHD4
We show that ADNP functions as an important chromatin regulator or genome organizer by association with two distinct chromatin regulators, BRG1 and CHD4

Summary

Introduction

Embryonic stem cells (ESCs) possess an epigenome and chromatin structures that are required for the maintenance of self-renewal and pluripotency. Activity Dependent Neuroprotective Protein was first described as a neuroprotective protein and has been implicated in various rare neural developmental disorders and ADNP Controls Gene Expression cancers, including the Helsmoortel-Van der Aa syndrome, gastric and colorectal cancers (Pinhasov et al, 2003; Vandeweyer et al, 2014). ADNP deficiency in pluripotent P19 cells leads to aberrant gene activity, functioning as both transcriptional activator and repressor (Gozes et al, 2015). A growing body of research has shown that ADNP functions as an important chromatin regulator by physical association with chromatin remodelers. ADNP was shown to interact with core sub-units of the SWI/SNF chromatin remodeling complex such as BRG1 and BAF250 (Mandel and Gozes, 2007). It has been shown that ADNP regulates local chromatin architecture by competing for binding with CTCF, a master genome architecture protein (Phillips-Cremins et al, 2013; Kaaij et al, 2019)

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