Intragenic transcriptional interference regulates the human immune ligand
            <scp>MICA</scp>

Lin, Dazhen; Hiron, Thomas K.; O’Callaghan, Chris

doi:10.15252/embj.201797138

Cited by 15 publications

(15 citation statements)

References 75 publications

(92 reference statements)

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“…Throughout development, alternative promoters and alternative TSSs are activated leading to increased transcript diversity [4]. Several single-locus studies have demonstrated that TSS switching events occur via mechanisms similar to that described in yeast [30,79]. In addition, diseases such as cancers and neurodevelopmental disorders such as autism and epilepsy are associated with pervasive misregulation of alternative promoters [80,81].…”

Section: Discussionmentioning

confidence: 99%

High-resolution analysis of cell-state transitions in yeast suggests widespread transcriptional tuning by alternative starts

et al. 2021

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Background The start and end sites of messenger RNAs (TSSs and TESs) are highly regulated, often in a cell-type-specific manner. Yet the contribution of transcript diversity in regulating gene expression remains largely elusive. We perform an integrative analysis of multiple highly synchronized cell-fate transitions and quantitative genomic techniques in Saccharomyces cerevisiae to identify regulatory functions associated with transcribing alternative isoforms. Results Cell-fate transitions feature widespread elevated expression of alternative TSS and, to a lesser degree, TES usage. These dynamically regulated alternative TSSs are located mostly upstream of canonical TSSs, but also within gene bodies possibly encoding for protein isoforms. Increased upstream alternative TSS usage is linked to various effects on canonical TSS levels, which range from co-activation to repression. We identified two key features linked to these outcomes: an interplay between alternative and canonical promoter strengths, and distance between alternative and canonical TSSs. These two regulatory properties give a plausible explanation of how locally transcribed alternative TSSs control gene transcription. Additionally, we find that specific chromatin modifiers Set2, Set3, and FACT play an important role in mediating gene repression via alternative TSSs, further supporting that the act of upstream transcription drives the local changes in gene transcription. Conclusions The integrative analysis of multiple cell-fate transitions suggests the presence of a regulatory control system of alternative TSSs that is important for dynamic tuning of gene expression. Our work provides a framework for understanding how TSS heterogeneity governs eukaryotic gene expression, particularly during cell-fate changes.

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Section: Discussionmentioning

confidence: 99%

High-resolution analysis of cell-state transitions in yeast suggests widespread transcriptional tuning by alternative starts

et al. 2021

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“…A prime example may turn out to be plant light signaling that relies on alternative TSS choices [49], as we observed for the AT4G15260 gene. Furthermore, recent examples of gene regulation by the act of interfering lncRNA transcription in yeast and human emphasize a key role for FACT [7, 37, 38]. While such examples remain to be characterized in plants, we demonstrate that the underlying mechanism of repressive RNAPII transcription is operational.…”

Section: Discussionmentioning

confidence: 64%

Transcription-driven chromatin repression of Intragenic transcription start sites

et al. 2019

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Progression of RNA polymerase II (RNAPII) transcription relies on the appropriately positioned activities of elongation factors. The resulting profile of factors and chromatin signatures along transcription units provides a “positional information system” for transcribing RNAPII. Here, we investigate a chromatin-based mechanism that suppresses intragenic initiation of RNAPII transcription. We demonstrate that RNAPII transcription across gene promoters represses their function in plants. This repression is characterized by reduced promoter-specific molecular signatures and increased molecular signatures associated with RNAPII elongation. The conserved FACT histone chaperone complex is required for this repression mechanism. Genome-wide Transcription Start Site (TSS) mapping reveals thousands of discrete intragenic TSS positions in fact mutants, including downstream promoters that initiate alternative transcript isoforms. We find that histone H3 lysine 4 mono-methylation (H3K4me1), an Arabidopsis RNAPII elongation signature, is enriched at FACT-repressed intragenic TSSs. Our analyses suggest that FACT is required to repress intragenic TSSs at positions that are in part characterized by elevated H3K4me1 levels. In sum, conserved and plant-specific chromatin features correlate with the co-transcriptional repression of intragenic TSSs. Our insights into TSS repression by RNAPII transcription promise to inform the regulation of alternative transcript isoforms and the characterization of gene regulation through the act of pervasive transcription across eukaryotic genomes.

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“…Although not applied in pre-clinical studies, a number of early works also suggest that dCas9-based methods can help circumvent other major tumor immunoevasion mechanisms. For instance, impairment of Treg immunosuppressive function by dCas9-KRAB-mediated forkhead box P3 (FoxP3) transcriptional repression, 139 , 140 dCas9-SAM-mediated enhancement of neoplastic transformation markers, such as MICA, 141 , 142 and dCas9-KRAB-directed repression of immunosuppressive cytokine receptors 143 have demonstrated that dCas9-mediated epigenetic engineering has potential in multiple facets of cancer immunotherapy. Ultimately, dCas9-mediated epigenetic editing to improve tumor immunogenicity and/or boost the host’s anti-tumor immune response opens new therapeutic avenues, particularly in combination with ICI or ACT therapies ( Figure 2 ).…”

Section: Epigenetic Editing By Crispr-dcas9 Can Improve Anti-tumor Host Immunitymentioning

confidence: 99%

Reprogramming the anti-tumor immune response via CRISPR genetic and epigenetic editing

Alves

Taifour

Dolcetti

et al. 2021

Molecular Therapy - Methods & Clinical Development

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Precise clustered regularly interspaced short palindromic repeats (CRISPR)-mediated genetic and epigenetic manipulation of the immune response has become a promising immunotherapeutic approach toward combating tumorigenesis and tumor progression. CRISPR-based immunologic reprograming in cancer therapy comprises the locus-specific enhancement of host immunity, the improvement of tumor immunogenicity, and the suppression of tumor immunoevasion. To date, the ex vivo re-engineering of immune cells directed to inhibit the expression of immune checkpoints or to express synthetic immune receptors (chimeric antigen receptor therapy) has shown success in some settings, such as in the treatment of melanoma, lymphoma, liver, and lung cancer. However, advancements in nuclease-deactivated CRISPR-associated nuclease-9 (dCas9)-mediated transcriptional activation or repression and Cas13-directed gene suppression present novel avenues for the development of tumor immunotherapies. In this review, the basis for development, mechanism of action, and outcomes from recently published Cas9-based clinical trial (genetic editing) and dCas9/Cas13-based pre-clinical (epigenetic editing) data are discussed. Lastly, we review cancer immunotherapy-specific considerations and barriers surrounding use of these approaches in the clinic.

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Intragenic transcriptional interference regulates the human immune ligand MICA

Cited by 15 publications

References 75 publications

High-resolution analysis of cell-state transitions in yeast suggests widespread transcriptional tuning by alternative starts

High-resolution analysis of cell-state transitions in yeast suggests widespread transcriptional tuning by alternative starts

Transcription-driven chromatin repression of Intragenic transcription start sites

Reprogramming the anti-tumor immune response via CRISPR genetic and epigenetic editing

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