Gene regulatory networks and epigenetic modifications in cell differentiation

Abstract

It is becoming increasingly clear that the functionalities of an organism are mostly derived from regulation of its gene repertoire. Specialized cell types are created from pluripotent stem cells by regulating expression of genes. In eukaryotes, genes are primarily regulated by gene regulatory networks consisting of highly sequence-specific transcription factors and epigenetic modifications. The former mode of regulation is more readily reversible and non-heritable across cell generations, whereas the latter mode is less reversible and heritable. In this article, we explore the relationship between cell differentiation and the two modes of regulation of gene expression, focusing primarily on pluripotent and multipotent stem cells. Recent studies suggest that stem cells execute different gene expression programs, probably driven by one or more gene regulatory network(s). It is now also evident that as stem cells differentiate to more specialized progeny cells, rewriting of epigenetic marks occurs in parallel with the change in the pattern of gene expression. A conceptual framework is put forward in which it is proposed that the cell fate determining gene regulatory network in a pluripotent or multipotent cell has the capability to exist in multiple stationary states with each stationary state dictating a particular pattern of gene expression. We also propose that the broad pattern of gene expression in each stationary state, termed the lineage biased state or LIBS, resembles that of a more differentiated progeny cell. The differentiation process leading to a particular progeny cell involves rewriting of epigenetic marks that result in upregulation of genes in a LIBS and silencing of genes involved in alternative LIBS; thus selecting a particular pattern of gene expression and making a lineage commitment. V C 2014 IUBMB Life, 66(2):100-109, 2014

Bi‐stability of the master gene regulatory network of the common dendritic precursor cell: Implications for cell differentiation

“…Previously, we have postulated that from a multipotent cell, lineage commitment to a successor state occurs through epigenetic silencing of core genes of other possible successor states. 12 Detailed knowledge of binding sites, gene expression patterns in the successor cells as well as the distribution of epigenetic marks would be essential to validate this hypothesis. The epigenetic modifications may also potentially have some influence on the GRN bi-stability if such modifications lead to alteration of the activity of GRN components.…”

“…11 We have previously hypothesized that a master GRN of a pluripotent or multi-potent cell possesses the multi-stationarity character, and each of the steady states is a precursor of a lineage-committed successor state. 12 The hypothesis also postulates that as cell differentiation proceeds toward a particular lineage-committed successor state, other successor states become inoperable due to epigenetic modifications of key genes, chromatin condensation, and other cellular processes. These processes restrict potency, resulting in one terminally differentiated successor state at the expense of others.…”

“…These processes restrict potency, resulting in one terminally differentiated successor state at the expense of others. [12][13][14] Dendritic cells or DCs are specialized antigenpresenting cells. 15 They originate from hematopoietic stem cells.…”

Asymmetry in indegree and outdegree distributions of gene regulatory networks arising from dynamical robustness

“…In actual gene regulatory networks, the connection weight w ij indicates that the ith gene has the binding motif of the j th gene in the regulatory region (promoter) in the genome. Moreover, the genomes of all cells in an individual are (almost) identical; therefore, the gene regulatory networks are essentially identical (however, connection strength can change by the effect of epigenetics [23]).…”

CDK11 safeguards the identity of human embryonic stem cells via fine‐tuning signaling pathways

“…It is important to elucidate the molecular mechanism by which hESCs sustain an undifferentiated state while retaining the ability to generate all cell types in the body. Previously, hESC research mainly focused on transcriptomes (Au & Sebastiano, 2014;Boyer et al, 2005;Fong, Cattoglio, Yamaguchi, & Tjian, 2012;Yeo & Ng, 2013), epigenetic regulation (Aloia, Di Stefano, & Di Croce, 2013;Boland, Nazor, & Loring, 2014;Kraushaar & Zhao, 2013;Roy & Kundu, 2014;Tee & Reinberg, 2014), and signaling pathways (Beattie et al, 2005;Bendall et al, 2007;Dalton, 2013;James, Levine, Besser, & Hemmati-Brivanlou, 2005;Lanner & Rossant, 2010;Singh et al, 2012;Vallier, Alexander, & Pedersen, 2005;Xu et al, 2005). It is well-known that OCT4, SOX2, and NANOG act as the core transcriptional factors for the maintenance of hESC self-renewal (Boyer et al, 2005).…”