Serine, Threonine and Tyrosine O-Acetylation in the Chromatin Landscape

Abstract

Histone post translational modifications (PTMs) are a key component of the dynamic and

responsive nucleoprotein structure that is chromatin. Assorted physiological processes

such as transcription and DNA repair are regulated by these histone PTMs and their

governing enzymes, as well as by the nucleosomal structure at the local gene site.

Downstream of signaling cascades, histone modifying enzymes can be recruited to add

specific histone marks, which serve as recruitment sites for DNA-binding proteins,

transcription factors, and chromatin remodeling complexes, which in turn modulate

transcription of crucial genes. With each new year, different histone marks are unveiled

with equally novel or groundbreaking physiological capabilities, which prompt two key

questions: (1) what other critical marks are there to be identified and (2) what new

mechanisms of chromatin function can be elucidated by characterizing these novel

variations within a prevalently studied biological system. In this study, quantitative mass

spectrometry was employed to identify novel serine, threonine and tyrosine O-acteylation

on histones. In the contexts of cellular reprogramming and cell cycle progression, histone

H3 serine 10 acetylation (H3S10ac) was observed to be enriched in pluripotent mouse

embryonic stem cells and during the DNA synthesis (S) phase of cell cycle. Chromatin

Immunoprecipitation followed by high-throughput DNA sequencing (ChIP-Seq) revealed

an enrichment of homeobox sequences at H3S10ac sites within the genome. In vitro

histone acetyltransferase (HAT) reactions, coupled with in vivo chemical inhibition,

uncovered p300, CREB-binding protein (CBP) and fungal Rtt109 as unique H3S10ac

HATs. Although H3S10ac is an invariably lower abundance mark, its enrichment in stem

cells compared to differentiated cells, mainly within homeobox motifs reiterates the precision of HAT enzymes for selecting their targets, as well as the potential impact of even lower level histone marks in epigenetic regulation. This discovery opens a doorway to further understanding epigenetic regulation in the context of cellular differentiation, and will hopefully encourage future studies of both combinatorial and individual histone modifications.