Inheritance of Repressed Chromatin Domains during S-phase Requires the Histone Chaperone NPM1

The epigenetic process safeguards cell identity during cell division through the inheritance of appropriate gene expression profiles. We demonstrated previously that parental nucleosomes are inherited by the same chromatin domains during DNA replication only in the case of repressed chromatin. We now show that this specificity is conveyed by NPM1, a histone H3/H4 chaperone. Proteomic analyses of late S-phase chromatin revealed NPM1 in association with both H3K27me3, an integral component of facultative heterochromatin and MCM2, an integral component of the DNA replication machinery; moreover NPM1 interacts directly with PRC2 and with MCM2. Given that NPM1 is essential, the inheritance of repressed chromatin domains was examined anew using mESCs expressing an auxin-degradable version of endogenous NPM1. Upon NPM1 degradation, cells accumulated in S-phase of the cell-cycle and parental nucleosome inheritance from repressed chromatin domains was markedly compromised. Appropriate inheritance required the NPM1 acidic patches that function in chaperone activity, pointing to NPM1 being integral to the epigenetic process.One-Sentence SummaryThe histone H3/H4 chaperone, NPM1, fosters epigenetic inheritance from parental repressed chromatin during DNA replication.

Waddington’s Processual Epigenetics and the Debate over Cryptic Variability

This chapter reappraises Waddington’s processual theory of epigenetics and examines its implications for contemporary evolutionary biology. It focuses in particular on the ontological difference between two conflicting assumptions that have been conflated in the recent debate over the nature of cryptic variability: a substance view that is consistent with the modern synthesis and construes variability as a preexisting pool of random genetic variation; and a processual view, which derives from Waddington’s conception of developmental canalization and understands variability as an epigenetic process. The chapter also discusses how these opposing interpretations fare in their capacity to explain the genetic assimilation of acquired characters.

The Emerging View of Aging as a Reversible Epigenetic Process

The achievement of animal cloning and subsequent development of cell reprogramming technology are having a profound impact on our view of the mechanisms of aging in complex organisms. The experimental evidence showing that an adult somatic nucleus implanted into an enucleated oocyte can give rise to a whole new individual strongly suggests that the integrity of the genome of an adult nucleus is fully preserved. Here, we will review recent experimental evidence showing that pluripotency gene-based cell reprogramming can erase the epigenetic marks of aging and rejuvenate cells from old individuals reversing most signs of aging and that when induced pluripotent stem cells are differentiated back to the cell type of origin, the rejuvenated cells share many of the features of wild-type counterparts from young donors. This evidence supports the idea that progressive epigenetic dysregulation may be the key driver of organismal aging and challenges the conventional view of aging as an irreversible process. The model of aging as an epigenetic process provides an elegant explanation of a number of age-related processes difficult to explain by conventional theories of aging.

A mechanistic role for DNA methylation in endothelial cell (EC)-enriched gene expression: relationship with DNA replication timing

Key Points Promoter DNA methylation, an epigenetic process, is functionally relevant for regulating the expression of endothelial cell–enriched genes.

COMPUTATION BY ANNOTATION: MODELLING EPIGENETIC REGULATION

We present a formal model inspired by the epigenetic process of gene annotation via histone modification. In particular, we study the generative capacity of a system in which annotations on a set of strings control which substrings are ultimately produced by the system and in which only the annotations, and not the strings themselves, may be rewritten. On a biological level this represents a first attempt to better understand the computational limits of this form of epigenetic regulation. We introduce two different derivation modes for our formal system and show that these systems are actually quite weak. The weaker of the derivation modes is directly capable only of generating a subset of the regular languages while the more powerful derivation mode is also only capable of generating all regular languages modulo a begin- and an end-marker.