Maintaining Cell Identity through Global Control of Genomic Organization

Abstract

Cell differentiation entails early lineage choices leading to the activation, and the subsequent maintenance, of the gene expression program characteristic of each cell type. Alternative lineage choices involve the activation of different regulatory and coding regions of the genome, a process instructed by lineage-determining transcription factors, and at least in part mediated by the deposition of chromatin marks that modify functionality and accessibility of the underlying genome. According to classic epigenetics, subsequent maintenance of chromatin marks across mitoses and in spite of environmental perturbations occurs largely through autonomous and unsupervised mechanisms. However, paradigmatic genetic and biochemical studies in immune system and hematopoietic cells strongly point to the concept that both induction and maintenance of the differentiated state require constant supervision by lineage-determining transcription factors, which may act to globally organize the genome in both the one- and the three-dimensional space.

High-throughput and quantitative assessment of enhancer activity in mammals by CapStarr-seq

“…Tissuespecific gene regulation is thought to be achieved by the combinatorial effect of multiple enhancers 22 . Hence, we asked whether analysis of additive enhancer strength could provide functional information concerning the regulated genes.…”

Transcriptional control of macrophage diversity and specialization

“…2). These observations provide a rationale for how cell-specific and stimulus-induced gene expression is regulated by enhancers, that is through the integrated action of (i) constitutively active but cell-restricted and (ii) inducible but ubiquitous TFs [12]. In a reciprocal manner, it will be interesting to determine if and how external stimuli alter and remodel the enhancer repertoire, leading to the acquisition of novel functional properties.…”

“…M2 macrophages are characterized by their high expression of markers of alternative activation, including arginase-1 (Arg1), chitinase-like Ym1 (Chi3l3), found in inflammatory zone 1 (Fizz1), mannose receptor (MR), chemokines such as CCL17, CCD24 and so on [9][10][11][12][13]. The pattern-recognition receptor system responsible for the recognition of helminth infection and M2 polarization has yet to be identified; however, stimulation of macrophages with the Th2 cytokines IL-4 or IL-13 induces M2-type macrophages [4,14].…”

“…Importantly, both processes are globally orchestrated by TFs acting to regulate the way chromatinized genomes are organized in order to enable a precise control over the final transcriptional output [12]. These emerging functionalities of TFs allow the definition of additional regulatory levels of gene expression, lying well upstream of biochemical signal transduction pathways induced by stimulation.…”

Accumulation of Specific Epigenetic Abnormalities During Development and Progression of T Cell Leukemia/Lymphoma

“…Epigenetic regulatory mechanisms are a central system to control the differentiation and function of the immune system and to ensure an appropriate gene expression profile in immune cells (Natoli G, 2010). This mechanism changes the gene expression profile, permitting cells to adapt to multiple environmental pressures.…”