The NSL complex-mediated nucleosome landscape is required to maintain transcription fidelity and suppression of transcription noise.

Kin Chung Lam,Giuseppe Semplicio,Ho-Ryun Chung,Herbert Holz,Shantanu S Iyer,Vivek Bhardwaj,Aline Gaub,Asifa Akhtar,Plamen Georgiev

doi:10.1101/gad.321489.118

Abstract

Nucleosomal organization at gene promoters is critical for transcription, with a nucleosome-depleted region (NDR) at transcription start sites (TSSs) being required for transcription initiation. How NDRs and the precise positioning of the +1 nucleosomes are maintained on active genes remains unclear. Here, we report that the Drosophila nonspecific lethal (NSL) complex is necessary to maintain this stereotypical nucleosomal organization at promoters. Upon NSL1 depletion, nucleosomes invade the NDRs at TSSs of NSL-bound genes. NSL complex member NSL3 binds to TATA-less promoters in a sequence-dependent manner. The NSL complex interacts with the NURF chromatin remodeling complex and is necessary and sufficient to recruit NURF to target promoters. Not only is the NSL complex essential for transcription, but it is required for accurate TSS selection for genes with multiple TSSs. Furthermore, loss of the NSL complex leads to an increase in transcriptional noise. Thus, the NSL complex establishes a canonical nucleosomal organization that enables transcription and determines TSS fidelity.

Highlights

Chromatin structure and organization are fundamental to the regulation of gene transcription
Because the nonspecific lethal (NSL) complex is an important regulator for the majority of active promoters (Lam et al 2012; Chelmicki et al 2014), we sought to understand its roles in establishing the chromatin landscape at promoters
To study if the NSL complex is required for nucleosomal organization, we knocked down NSL1 and GST in Drosophila S2 embryonic cells and performed micrococcal nuclease digestion followed by high-throughput sequencing (MNase-seq) (Fig. 1A; Supplemental Fig. S1A–C)

Summary

Introduction

Chromatin structure and organization are fundamental to the regulation of gene transcription. Compared with focused promoters of tissue-specific genes, dispersed housekeeping gene promoters contain distinct sets of core promoter motifs and binding proteins (Vo Ngoc et al 2017). Each remodeler has its characteristic molecular structure, target genomic locations, and roles in cells In higher eukaryotes, it is not yet clear which trans-acting factors are responsible for the nucleosomal organization at TSSs. How chromatin remodeling complexes work in concert with other chromatin-modifying enzymes and transcription machinery to facilitate the transcription process remains an active area of research (Struhl and Segal 2013; Lai and Pugh 2017)

Methods

Results

Conclusion