An inflammatory response is initiated by the temporally controlled activation of genes encoding a broad range of regulatory and effector proteins. A central goal is to devise strategies for the ...selective modulation of proinflammatory gene transcription, to allow the suppression of genes responsible for inflammation-associated pathologies while maintaining a robust host response to microbial infection. Toward this goal, recent studies have revealed an unexpected level of diversity in the mechanisms by which chromatin structure and individual transcription factors contribute to the selective regulation of inflammatory genes.
Members of the NF-κB family of transcription factors function as dominant regulators of inducible gene expression in almost all cell types in response to a broad range of stimuli, with particularly ...important roles in coordinating both innate and adaptive immunity. This review summarizes the present knowledge and recent progress toward elucidating the numerous regulatory layers that confer target-gene selectivity in response to an NF-κB-inducing stimulus.
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Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Macrophages respond to inflammatory stimuli by modulating the expression of hundreds of genes in a defined temporal cascade, with diverse transcriptional and posttranscriptional mechanisms ...contributing to the regulatory network. We examined proinflammatory gene regulation in activated macrophages by performing RNA-seq with fractionated chromatin-associated, nucleoplasmic, and cytoplasmic transcripts. This methodological approach allowed us to separate the synthesis of nascent transcripts from transcript processing and the accumulation of mature mRNAs. In addition to documenting the subcellular locations of coding and noncoding transcripts, the results provide a high-resolution view of the relationship between defined promoter and chromatin properties and the temporal regulation of diverse classes of coexpressed genes. The data also reveal a striking accumulation of full-length yet incompletely spliced transcripts in the chromatin fraction, suggesting that splicing often occurs after transcription has been completed, with transcripts retained on the chromatin until fully spliced.
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► Coding and noncoding transcripts exhibit characteristic subcellular distributions ► The most potently induced genes favor promoters with low CpG content ► Full-length, incompletely spliced transcripts accumulate on the chromatin ► Delayed transcript release may reflect a requirement for the completion of splicing
Sequencing analysis of subcellular fractions allows the separation of synthesis of nascent transcripts from RNA processing and the accumulation of mature mRNAs, revealing a high-resolution view of transcript dynamics of proinflammatory genes. Surprisingly, full-length yet incompletely spliced transcripts accumulate on chromatin, suggesting that splicing often follows the completion of transcription.
A fundamental feature of the transcriptional response to an nuclear factor‐κB (NF‐κB)‐inducing stimulus is that the response is highly selective and limited to the activation of only a subset of ...potential NF‐κB target genes. One major contributor to selectivity of the response is likely to be the capacity of different NF‐κB dimers to regulate different sets of target genes. The NF‐κB family of transcription factors consists of five proteins, RelA, c‐Rel, RelB, p50, and p52, which assemble into several homodimeric and heterodimeric species. Studies of mutant mouse strains have revealed that each family member, and perhaps each dimer, carries out unique functions in regulating transcription in cells of the immune system and in many other cell types. Dimer‐specific functions can be conferred by selective protein–protein interactions with other transcription factors, coregulatory proteins, and chromatin proteins. Unique DNA‐binding specificities and affinities make additional contributions to selectivity of the response, with growing evidence that some NF‐κB dimers can adopt different conformations and thereby function differently when bound to different DNA sequences. Despite significant advances, our knowledge remains limited and many years of additional work will be needed to fully understand how the dimer‐specific functions of NF‐κB contribute to transcriptional selectivity.
A fundamental property of cells of the innate immune system is their ability to elicit a transcriptional response to a microbial stimulus or danger signal with a high degree of cell type and stimulus ...specificity. The selective response activates effector pathways to control the insult and plays a central role in regulating adaptive immunity through the differential regulation of cytokine genes. Selectivity is dictated by signaling pathways and their transcription factor targets. However, a growing body of evidence supports models in which different subsets of genes exhibit distinct chromatin features that play active roles in shaping the response. Chromatin also participates in innate memory mechanisms that can promote tolerance to a stimulus or prime cells for a more robust response. These findings have generated interest in the capacity to modulate chromatin regulators with small-molecule compounds for the treatment of diseases associated with innate or adaptive immunity.
Much has been learned about the genes and pathways that contribute to a diverse array of hematopoietic malignancies and other hematopoietic diseases. However, for many of these diseases, an ...allogeneic hematopoietic stem cell (HSC) transplant remains the preferred treatment option. This opinion article provides the perspective of a molecular immunologist who became a transplant patient after many years studying basic mechanisms of blood cell development. Among many lessons learned were the magnitude of racial and ethnic disparities in donor registries, the substantial improvement in outcomes over time that were due to the collective impact of numerous advances, the benefits and limitations of genetic and clinical data, and the remarkably intricate balance between promoting graft-versus-disease activity of donor cells while suppressing graft-versus-host disease (GVHD).
Allogeneic hematopoietic stem cell (HSC) transplants are frequently the preferred treatment option for a broad range of hematopoietic malignancies and other hematopoietic disorders.International HSC donor registries allow patients to find human leukocyte antigen (HLA)-matched donors, but substantial racial and ethnic disparities exist that must be addressed.Allogeneic transplant outcomes have improved dramatically due to the collective impact of numerous improvements in pretransplant conditioning and post-transplant support.Histological, cytogenetic, and genetic data allow hematopoietic disorders to be classified and sometimes provide useful information about treatment options, but are often less informative than hoped.A major challenge after an HSC transplant is to strike an appropriate balance for each hematopoietic malignancy patient between suppressing graft-versus-host disease while promoting the elimination of residual diseased cells by the graft-versus-disease activity of donor cells.
Activation of Toll-like receptor (TLR) signaling and related pathways by microbial products drives inflammatory responses, host-defense pathways and adaptive immunity. The cost of excessive ...inflammation is cell and tissue damage, an underlying cause of many acute and chronic diseases. Coincident with activation of TLR signaling, a plethora of anti-inflammatory pathways and mechanisms begin to modulate inflammation until tissue repair is complete. Whereas most studies have focused on the signaling components immediately downstream of the TLRs, this Review summarizes the different levels of anti-inflammatory pathways that have evolved to abate TLR signaling and how they are integrated to prevent cell and tissue destruction.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Highlights ► Transcriptional selectivity can be influenced by diverse coregulatory interactions of individual transcription factors. ► Cell-type specificity of induction is directly influenced by key ...regulators of lineage commitment. ► Promoter architecture and chromatin structure make major contributions to transcriptional selectivity.
Most studies of tissue-specific and developmental stage-specific transcription have focused on the DNA motifs, transcription factors, or chromatin events required for the active transcription of a ...gene in cells in which the gene is expressed, or for its active or heritable silencing in nonexpressing cells. However, accumulating evidence suggests that, in multicellular eukaryotes, enhancers or promoters for tissue-specific genes interact with pioneer transcription factors in embryonic stem cells and at other early stages of development, long before the genes are transcribed. These early interactions, which can lead to the presence of unmethylated CpG dinucleotides, histone modification signatures, and/or chromatin remodeling, may carry out different functions at different classes of genes.
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