The MHC class I gene, PD1, has neither functional TATAA nor Initiator (Inr) elements in its core promoter and initiates transcription at multiple, dispersed sites over an extended region in vitro. Here, we define a novel core promoter feature that supports regulated transcription through selective transcription start site (TSS) usage. We demonstrate that TSS selection is actively regulated and context dependent. Basal and activated transcriptions initiate from largely nonoverlapping TSS regions. Transcripts derived from multiple TSS encode a single protein, due to the absence of any ATG triplets within ∼430 bp upstream of the major transcription start site. Thus, the PD1 core promoter is embedded within an “ATG desert.” Remarkably, extending this analysis genome-wide, we find that ATG deserts define a novel promoter subclass. They occur nonrandomly, are significantly associated with non-TATAA promoters that use multiple TSS, independent of the presence of CpG islands (CGI). We speculate that ATG deserts may provide a core promoter platform upon which complex upstream regulatory signals can be integrated, targeting multiple TSS whose products encode a single protein.
To examine the role of chromatin in transcriptional regulation of the major histocompatibility complex (MHC) class I gene, we determined nucleosome occupancy and positioning, histone modifications, and H2A.Z occupancy across its regulatory region in murine tissues that have widely different expression levels. Surprisingly, nucleosome occupancy and positioning were indistinguishable between the spleen, kidney, and brain. In all three tissues, the 200 bp upstream of the transcription start site had low nucleosome occupancy. In contrast, nuclease hypersensitivity, histone modifications, and H2A.Z occupancy showed tissue-specific differences. Thus, tissue-specific differences in MHC class I transcription correlate with histone modifications and not nucleosomal organization. Further, activation of class I transcription by gamma interferon or its inhibition by ␣-amanitin did not alter nucleosome occupancy, positioning, nuclease hypersensitivity, histone modifications, or H2A.Z occupancy in any of the tissues examined. Thus, chromatin remodeling was not required to dynamically modulate transcriptional levels. These findings suggest that the MHC class I promoter remains poised and accessible to rapidly respond to infection and environmental cues.Accurate gene expression is the result of diverse transcriptional responses to both tissue-specific "intrinsic" and dynamic "extrinsic" stimuli. In particular, widely expressed genes, including members of the major histocompatibility complex (MHC) class I family, are regulated by complex and overlapping developmental, tissue-specific, and inducible stimuli. Although MHC class I genes are ubiquitously expressed, distinct tissue-specific regulatory mechanisms lead to dramatically different levels of expression (55). For example, MHC class I levels in neural tissues and germ line cells are approximately 2 orders of magnitude lower than in lymphoid tissues. Further, numerous extracellular stimuli, in particular hormones and cytokines, are capable of dynamically modulating intrinsic tissue-specific MHC class I expression patterns (55). For example, gamma interferon (IFN-␥) increases class I transcription in nearly all tissues, whereas thyroid-stimulating hormone decreases it. The mechanisms that integrate these intrinsic and extrinsic regulatory signals are only partially understood.MHC class I expression is primarily regulated at the transcriptional level, and many of the DNA sequence elements that mediate both tissue-specific and hormonal/cytokine regulation have been identified. Tissue-specific expression is achieved through the combined effects of a promoter-distal complex regulatory element and a series of promoter-proximal elements. The promoter-distal element, located between bp Ϫ700 and Ϫ800, consists of overlapping enhancer and silencer elements (63). Hormone/cytokine signaling is mediated by a series of promoter-proximal elements, located between bp Ϫ68 and Ϫ500. These elements include enhancer A (6,17,18,26,59), IFN-␥-stimulated response element (2,16,19,20,28,62), and a c...
The MYC proto‐oncogene and BRD4, a BET family protein, are two cardinal proteins that have a broad influence in cell biology and disease. Both proteins are expressed ubiquitously in mammalian cells and play central roles in controlling growth, development, stress responses and metabolic function. As chromatin and transcriptional regulators, they play a critical role in regulating the expression of a burgeoning array of genes, maintaining chromatin architecture and genome stability. Consequently, impairment of their function or regulation leads to many diseases, with cancer being the most predominant. Interestingly, accumulating evidence indicates that regulation of the expression and functions of MYC are tightly intertwined with BRD4 at both transcriptional and post‐transcriptional levels. Here, we review the mechanisms by which MYC and BRD4 are regulated, their functions in governing various molecular mechanisms and the consequences of their dysregulation that lead to disease. We present a perspective of how the regulatory mechanisms for the two proteins could be entwined at multiple points in a BRD4‐MYC nexus that leads to the modulation of their functions and disease upon dysregulation.
Regulation of MHC class I gene expression is critical to achieve proper immune surveillance. In this work, we identify elements downstream of the MHC class I promoter that are necessary for appropriate in vivo regulation: a novel barrier element that protects the MHC class I gene from silencing and elements within the first two introns that contribute to tissue specific transcription. The barrier element is located in intergenic sequences 3′ to the polyA addition site. It is necessary for stable expression in vivo, but has no effect in transient transfection assays. Accordingly, in both transgenic mice and stably transfected cell lines, truncation of the barrier resulted in transcriptional gene silencing, increased nucleosomal density and decreased histone H3K9/K14 acetylation and H3K4 di-methylation across the gene. Significantly, distinct sequences within the barrier element govern anti-silencing and chromatin modifications. Thus, this novel barrier element functions to maintain transcriptionally permissive chromatin organization and prevent transcriptional silencing of the MHC class I gene, ensuring it is poised to respond to immune signaling.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.