Dataset Information

Histone modifications, but not nucleosomal positioning, correlate with major histocompatibility complex class I promoter activity in different tissues in vivo.

ABSTRACT: 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 alpha-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.

SUBMITTER: Kotekar AS

PROVIDER: S-EPMC2593446 | biostudies-literature | 2008 Dec

REPOSITORIES: biostudies-literature

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Histone modifications, but not nucleosomal positioning, correlate with major histocompatibility complex class I promoter activity in different tissues in vivo.

Kotekar Aparna S AS Weissman Jocelyn D JD Gegonne Anne A Cohen Helit H Singer Dinah S DS

Molecular and cellular biology 20080922 24

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 ha ...[more]

PMID: 18809568

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Project description:Sirenians share with cetaceans and pinnipeds several convergent traits selected for the aquatic lifestyle. Living in water poses new challenges not only for locomotion and feeding but also for combating new pathogens, which may render the immune system one of the best tools aquatic mammals have for dealing with aquatic microbial threats. So far, only cetaceans have had their class II Major Histocompatibility Complex (MHC) organization characterized, despite the importance of MHC genes for adaptive immune responses. This study aims to characterize the organization of the marine mammal class II MHC using publicly available genomes. We located class II sequences in the genomes of one sirenian, four pinnipeds and eight cetaceans using NCBI-BLAST and reannotated the sequences using local BLAST search with exon and intron libraries. Scaffolds containing class II sequences were compared using dotplot analysis and introns were used for phylogenetic analysis. The manatee class II region shares overall synteny with other mammals, however most DR loci were translocated from the canonical location, past the extended class II region. Detailed analysis of the genomes of closely related taxa revealed that this presumed translocation is shared with all other living afrotherians. Other presumptive chromosome rearrangements in Afrotheria are the deletion of DQ loci in Afrosoricida and deletion of DP in E. telfairi. Pinnipeds share the main features of dog MHC: lack of a functional pair of DPA/DPB genes and inverted DRB locus between DQ and DO subregions. All cetaceans share the Cetartiodactyla inversion separating class II genes into two subregions: class IIa, with DR and DQ genes, and class IIb, with non-classic genes and a DRB pseudogene. These results point to three distinct and unheralded class II MHC structures in marine mammals: one canonical organization but lacking DP genes in pinnipeds; one bearing an inversion separating IIa and IIb subregions lacking DP genes found in cetaceans; and one with a translocation separating the most diverse class II gene from the MHC found in afrotherians and presumptive functional DR, DQ, and DP genes. Future functional research will reveal how these aquatic mammals cope with pathogen pressures with these divergent MHC organizations.

Project description:BackgroundControlled modulation of nucleosomal DNA accessibility via post-translational modifications (PTM) is a critical component to many cellular functions. Charge-altering PTMs in the globular histone core-including acetylation, phosphorylation, crotonylation, propionylation, butyrylation, formylation, and citrullination-can alter the strong electrostatic interactions between the oppositely charged nucleosomal DNA and the histone proteins and thus modulate accessibility of the nucleosomal DNA, affecting processes that depend on access to the genetic information, such as transcription. However, direct experimental investigation of the effects of these PTMs is very difficult. Theoretical models can rationalize existing observations, suggest working hypotheses for future experiments, and provide a unifying framework for connecting PTMs with the observed effects.ResultsA physics-based framework is proposed that predicts the effect of charge-altering PTMs in the histone core, quantitatively for several types of lysine charge-neutralizing PTMs including acetylation, and qualitatively for all phosphorylations, on the nucleosome stability and subsequent changes in DNA accessibility, making a connection to resulting biological phenotypes. The framework takes into account multiple partially assembled states of the nucleosome at the atomic resolution. The framework is validated against experimentally known nucleosome stability changes due to the acetylation of specific lysines, and their effect on transcription. The predicted effect of charge-altering PTMs on DNA accessibility can vary dramatically, from virtually none to a strong, region-dependent increase in accessibility of the nucleosomal DNA; in some cases, e.g., H4K44, H2AK75, and H2BK57, the effect is significantly stronger than that of the extensively studied acetylation sites such H3K56, H3K115 or H3K122. Proximity to the DNA is suggestive of the strength of the PTM effect, but there are many exceptions. For the vast majority of charge-altering PTMs, the predicted increase in the DNA accessibility should be large enough to result in a measurable modulation of transcription. However, a few possible PTMs, such as acetylation of H4K77, counterintuitively decrease the DNA accessibility, suggestive of the repressed chromatin. A structural explanation for the phenomenon is provided. For the majority of charge-altering PTMs, the effect on DNA accessibility is simply additive (noncooperative), but there are exceptions, e.g., simultaneous acetylation of H4K79 and H3K122, where the combined effect is amplified. The amplification is a direct consequence of the nucleosome-DNA complex having more than two structural states. The effect of individual PTMs is classified based on changes in the accessibility of various regions throughout the nucleosomal DNA. The PTM's resulting imprint on the DNA accessibility, "PTMprint," is used to predict effects of many yet unexplored PTMs. For example, acetylation of H4K44 yields a PTMprint similar to the PTMprint of H3K56, and thus acetylation of H4K44 is predicted to lead to a wide range of strong biological effects.ConclusionCharge-altering post-translational modifications in the relatively unexplored globular histone core may provide a precision mechanism for controlling accessibility to the nucleosomal DNA.

Dataset Information

Histone modifications, but not nucleosomal positioning, correlate with major histocompatibility complex class I promoter activity in different tissues in vivo.

Publications

Histone modifications, but not nucleosomal positioning, correlate with major histocompatibility complex class I promoter activity in different tissues in vivo.

Similar Datasets

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