Emerging roles of histone modifications and HDACs in RNA splicing.

Raneen Rahhal,Edward Seto

doi:10.1093/nar/gkz292

Abstract

Histone modifications and RNA splicing, two seemingly unrelated gene regulatory processes, greatly increase proteome diversity and profoundly influence normal as well as pathological eukaryotic cellular functions. Like many histone modifying enzymes, histone deacetylases (HDACs) play critical roles in governing cellular behaviors and are indispensable in numerous biological processes. While the association between RNA splicing and histone modifications is beginning to be recognized, a lack of knowledge exists regarding the role of HDACs in splicing. Recent studies however, reveal that HDACs interact with spliceosomal and ribonucleoprotein complexes, actively control the acetylation states of splicing-associated histone marks and splicing factors, and thereby unexpectedly could modulate splicing. Here, we review the role of histone/protein modifications and HDACs in RNA splicing and discuss the convergence of two parallel fields, which supports the argument that HDACs, and perhaps most histone modifying enzymes, are much more versatile and far more complicated than their initially proposed functions. Analogously, an HDAC-RNA splicing connection suggests that splicing is regulated by additional upstream factors and pathways yet to be defined or not fully characterized. Some human diseases share common underlying causes of aberrant HDACs and dysregulated RNA splicing and, thus, further support the potential link between HDACs and RNA splicing.

Highlights

The human genome is comprised of ∼3.2 billion nucleotides, of which only 1.5% codes for proteins [1,2]
Alternative splicing is the process by which different regions of exons and introns are joined together to produce mature messenger RNA transcripts, which often lead to unique proteins or isoforms
The main splicing machinery is the major spliceosome, a megadalton complex composed of five uridine-rich small nuclear RNAs––U1, U2, U4, U5 and U6 (RNU1, RNU2, RNU4, RNU5 and RNU6)––as well as nearly 150 associated proteins, forming small nuclear ribonucleoproteins [8]

Summary

Introduction

The human genome is comprised of ∼3.2 billion nucleotides, of which only 1.5% codes for proteins [1,2]. It is intriguing to speculate that HDACs could multi-task by regulating the gene expression of many non-histone proteins through modulating RNA splicing and subsequently modifying those same proteins through post-translational deacetylation.

Results

Conclusion