Connecting Transcriptional Control to Chromosome Structure and Human Disease

Abstract

Embryonic stem cells (ESCs) provide an attractive model system for studying the transcriptional control of cell state. Their two key properties self-renewal and pluripotency allow them to be propagated almost indefinitely in culture, yet differentiate into any cell type in the body (Fig. 1). Although the regulatory networks that give rise to the various cell states are highly complex, a number of simple regulatory concepts have emerged from studies of ESC transcriptional control and cellular reprogramming. These concepts, which involve the roles of transcription factors, signal transduction pathways, and regulators of chromatin structure in the control of cell state, are not necessarily limited to ESCs and may apply to all cell types. TRANSCRIPTION FACTORS AND CONTROL OF ESC STATE DNA-binding transcriptional regulators are key to specific gene control. Early studies into the transcriptional control of the Escherichia coli lac operon created a framework for understanding gene control in all of biology (Jacob and Monod 1961). In the absence of lactose, the lac operon is repressed by the lac repressor, a DNA-binding protein that binds specifically to a DNA element just downstream from the transcription start site called the lac operator. When the repressor is bound to the lac operator, transcription initiation by RNA polymerase is inhibited. If lactose is present, it is metabolized into allolactose, which binds the lac repressor protein and alters its conformation, thus preventing it from binding to the lac operator, and allowing transcription to occur. A second control mechanism , that involves sensing of the nutrient environment and a second DNA-binding transcriptional regulator, can contribute to further activation of the lac operon in the absence of glucose. Cyclic adenosine monophosphate (cAMP) is a signaling molecule whose prevalence is inversely propor-We review key insights into transcriptional regulation of cell state that have emerged from the study of embryonic stem cells. These insights are described in the context of historical studies of the roles of transcription factors, signal transduction pathways , and regulators of chromatin structure. We highlight recent studies that have led to the model that mediator and cohesin physically and functionally connect the enhancers and core promoters of a key subset of active genes in cells, thus generating cell-type-specific DNA loops linked to the gene-expression program of each cell. Mutations in the genes encoding mediator and cohesin components can cause an array of human developmental syndromes and diseases, and we discuss the implications of these findings for the mechanisms involved in these diseases.

Functional roles of enhancer RNAs for oestrogen-dependent transcriptional activation

“…Despite the discovery of enhancers more than 35 years ago (1,2) , full understanding of the mechanisms by which they regulate gene expression has been a relatively resistant problem. Here, we have provided several lines of evidence that induced eRNA transcripts are functionally important for the actions of estrogen-regulated gene enhancers, at least in part by contributing to the dynamic generation/stabilization of enhancer:promoter looping between the regulated coding transcription units and these ERα-bound enhancers.…”

“… The functional importance of gene enhancers in regulated gene expression is well established (1–3) . In addition to widespread transcription of long non-coding RNAs (ncRNA) in mammalian cells (4–6) , bidirectional ncRNAs referred to as eRNAs are transcribed on enhancers (7–9) .…”

Role of Helicase-Like Transcription Factor (Hltf) in the G2/M Transition and Apoptosis in Brain

“…In the Hltf null brain, reduced mRNA expression of Rad21/Scc1 is expected to disrupt the cohesin ring and cause asynchronous anaphase [55]. Also, reduced Rad21/Scc1 mRNA has the potential to compromise the availability of cohesin in DNA looping to regulate transcription [56].…”

Cohesins and Cohesin-Regulators in Meiosis

“…This result suggests that Scc2 could play a dual role in gene regulation and sister-chromatid cohesion during meiotic differentiation. Although the mechanism is poorly understood yet, the role of cohesins and cohesion cofactors in gene regulation has been largely studied in the somatic line (Chien et al, 2011, Dorsett, 2011, Newman & Young, 2010, Ong & Corces, 2011. However, meiosis-specific gene regulation is a future field of study where probably different groups are work in.…”