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Abstract: More than 70% of breast cancers in women require estrogens for cell proliferation and survival. 17β-estradiol (E2) effect on mammary target cells is almost exclusively mediated by its binding to the estrogen receptor-α (ERα) that joins chromatin where it assembles active transcription complexes. The proliferative and pro-survival action of estrogens is antagonized in most cases by retinoic acid (RA), even though the cognate retinoic acid receptor-α (RARα) cooperates with ERα on promoters of estrogen-responsive genes. We have examined at the molecular level the crosstalk between these nuclear receptors from the point of view of their control of cell growth and show here that RA reverts estrogen-stimulated transcription of the pivotal anti-apoptotic bcl-2 gene by preventing demethylation of dimethyl lysine 9 in histone H3 (HeK9me2). As we previously reported, this is obtained by means of E2-triggered activation of the lysine-specific demethylase 1 (LSD1), an enzyme that manages chromatin plasticity in order to allow specific movements of chromosomal regions within the nucleus. We find that E2 fuels LSD1 by inducing migration of the catalytic subunit of protein kinase A (PKA) into the nucleus, where it targets estrogen-responsive loci. RA rescues LSD1-dependent disappearance of H3K9me2 at bcl-2 regulatory regions upon the prevention of PKA assembly to the same sites. [Copyright &y& Elsevier]

Abstract: The retention of transcription proteins at an actively transcribed gene contributes to maintenance of the active transcriptional state and increases the rate of subsequent transcription cycles relative to the initial cycle. This process, called transcription reinitiation, generates the abundant RNAs in living cells. The persistence of stable preinitiation intermediates on activated genes representing at least a subset of basal transcription components has long been recognized as a shared feature of RNA polymerase (Pol) I, II and III-dependent transcription in eukaryotes. Studies of the Pol III transcription machinery and its target genes in eukaryotic genomes over the last fifteen years, has uncovered multiple details on transcription reinitiation. In addition to the basal transcription factors that recruit the polymerase, Pol III itself can be retained on the same gene through multiple transcription cycles by a facilitated recycling pathway. The molecular bases for facilitated recycling are progressively being revealed with advances in structural and functional studies. At the same time, progress in our understanding of Pol III transcriptional regulation in response to different environmental cues points to the specific mechanism of Pol III reinitiation as a key target of signaling pathway regulation of cell growth. This article is part of a Special Issue entitled: Transcription by Odd Pols. [Copyright &y& Elsevier]

Abstract: The cycle of eukaryotic transcription, from initiation to elongation and termination is regulated at multiple steps. Coordinated action of regulatory factors keeps in check the transcriptional competence of RNA polymerase II (RNAPII) at different stages. Productive transcription requires the escape of the paused RNAPII from the promoter and transition to rapid elongation of the transcript. Numerous studies have identified diverse mechanisms of initiating transcription by overriding inhibitory signals at the gene promoter. The general theme that has emerged is that the balance between positive and negative regulatory factors determines the overall rate of transcription. Recently transcription termination has emerged as an important area of transcriptional regulation that is coupled with the efficient recycling of RNAPII. The factors associated with transcription termination can also mediate gene looping and thereby determine the efficiency of re-initiation. This review highlights these regulatory steps, the key modulators involved in transcription dynamics, and the emerging tools to analyze them. [Copyright &y& Elsevier]

The transcription cycle of RNAPII is comprised of three consecutive steps; initiation, elongation and termination. It has been assumed that the initiation and termination steps occur in spatial isolation, essentially as independent events. A growing body of evidence, however, has challenged this dogma. First, factors involved in initiation and termination exhibit both a genetic and a physical interaction during transcription. Second, the initiation and termination factors have been found to occupy both ends of a transcribing gene. Third, physical interaction of initiation and termination factors occupying distal ends of a gene sometime results in the entire terminator region of a genes looping back and contact its cognate promoter, thereby forming a looped gene architecture during transcription. A logical interpretation of these findings is that the initiation and termination steps of transcription do not occur in isolation. There is extensive communication of factors occupying promoter and terminator ends of a gene during transcription cycle. This review entails a discussion of the promoter-terminator crosstalk and its implication in the context of transcription. • Promoter and terminator crosstalk during transcription. • Crosstalk involves physical or functional interaction of initiation and termination factors. • Physical interaction of initiation factors at the promoter with the termination factors at the 3′ end of a gene may result in formation of a looped gene architecture. • Gene looping has been implicated in termination, reinitiation, promoter directionality and transcription memory. • Not all promoter-terminator crosstalk, however, results in gene loop formation. [ABSTRACT FROM AUTHOR]