scholarly journals Myeloid lncRNA LOUP Mediates Opposing Regulatory Effects of RUNX1 and RUNX1-ETO in t(8;21) AML

Blood ◽  
2021 ◽  
Author(s):  
Bon Q Trinh ◽  
Simone Ummarino ◽  
Yanzhou Zhang ◽  
Alexander K Ebralidze ◽  
Mahmoud A Bassal ◽  
...  
Keyword(s):  
Transcription Factors ◽  
Noncoding Rna ◽  
Gene Activation ◽  
Chromatin Accessibility ◽  
Specific Gene ◽  
Cell Type ◽  
Genome Wide ◽  
Therapeutic Development ◽  
Cell Type Specific ◽  
Regulatory Effects

The mechanism underlying cell type-specific gene induction conferred by ubiquitous transcription factors as well as disruptions caused by their chimeric derivatives in leukemia is not well understood. Here we investigate whether RNAs coordinate with transcription factors to drive myeloid gene transcription. In an integrated genome-wide approach surveying for gene loci exhibiting concurrent RNA- and DNA-interactions with the broadly expressed transcription factor RUNX1, we identified the long noncoding RNA LOUP. This myeloid-specific and polyadenylated lncRNA induces myeloid differentiation and inhibits cell growth, acting as a transcriptional inducer of the myeloid master regulator PU.1. Mechanistically, LOUP recruits RUNX1 to both the PU.1 enhancer and the promoter, leading to the formation of an active chromatin loop. In t(8;21) acute myeloid leukemia, wherein RUNX1 is fused to ETO, the resulting oncogenic fusion protein RUNX1-ETO limits chromatin accessibility at the LOUP locus, causing inhibition of LOUP and PU.1 expression. These findings highlight the important role of the interplay between cell type-specific RNAs and transcription factors as well as their oncogenic derivatives in modulating lineage-gene activation and raise the possibility that RNA regulators of transcription factors represent alternative targets for therapeutic development.

scholarly journals Myeloid lncRNA LOUP Mediates Opposing Regulatory Effects of RUNX1 and RUNX1-ETO in t(8;21) AML

2020 ◽  
Author(s):  
Bon Q. Trinh ◽  
Simone Ummarino ◽  
Alexander K. Ebralidze ◽  
Emiel van der Kouwe ◽  
Mahmoud A. Bassal ◽  
...  
Keyword(s):  
Transcription Factors ◽  
Cell Growth ◽  
Noncoding Rna ◽  
Gene Activation ◽  
Chromatin Accessibility ◽  
Myeloid Differentiation ◽  
Specific Gene ◽  
List Type ◽  
Cell Type ◽  
Cell Type Specific

ABSTRACTThe mechanism underlying cell type-specific gene induction conferred by ubiquitous transcription factors as well as disruptions caused by their chimeric derivatives in leukemia is not well understood. Here we investigate whether RNAs coordinate with transcription factors to drive myeloid gene transcription. In an integrated genome-wide approach surveying for gene loci exhibiting concurrent RNA- and DNA-interactions with the broadly expressed transcription factor RUNX1, we identified the long noncoding RNA LOUP. This myeloid-specific and polyadenylated lncRNA induces myeloid differentiation and inhibits cell growth, acting as a transcriptional inducer of the myeloid master regulator PU.1. Mechanistically, LOUP recruits RUNX1 to both the PU.1 enhancer and the promoter, leading to the formation of an active chromatin loop. In t(8;21) acute myeloid leukemia, wherein RUNX1 is fused to ETO, the resulting oncogenic fusion protein RUNX1-ETO limits chromatin accessibility at the LOUP locus, causing inhibition of LOUP and PU.1 expression. These findings highlight the important role of the interplay between cell type-specific RNAs and transcription factors as well as their oncogenic derivatives in modulating lineage-gene activation and raise the possibility that RNA regulators of transcription factors represent alternative targets for therapeutic development.KEY POINTSlncRNA LOUP coordinates with RUNX1 to induces PU.1 long-range transcription, conferring myeloid differentiation and inhibiting cell growth.RUNX1-ETO limits chromatin accessibility at the LOUP locus, causing inhibition of LOUP and PU.1 expression in t(8;21) AML.

scholarly journals Genetic influences on cell type specific gene expression and splicing during neurogenesis elucidate regulatory mechanisms of brain traits

2020 ◽  
Author(s):  
Nil Aygün ◽  
Angela L. Elwell ◽  
Dan Liang ◽  
Michael J. Lafferty ◽  
Kerry E. Cheek ◽  
...  
Keyword(s):  
Gene Expression ◽  
Regulatory Elements ◽  
Regulatory Mechanisms ◽  
Specific Gene ◽  
Cell Type ◽  
Specific Expression ◽  
Risk Variants ◽  
Allele Specific ◽  
Cell Type Specific ◽  
Regulatory Effects

SummaryInterpretation of the function of non-coding risk loci for neuropsychiatric disorders and brain-relevant traits via gene expression and alternative splicing is mainly performed in bulk post-mortem adult tissue. However, genetic risk loci are enriched in regulatory elements of cells present during neocortical differentiation, and regulatory effects of risk variants may be masked by heterogeneity in bulk tissue. Here, we map e/sQTLs and allele specific expression in primary human neural progenitors (n=85) and their sorted neuronal progeny (n=74). Using colocalization and TWAS, we uncover cell-type specific regulatory mechanisms underlying risk for these traits.

scholarly journals Distinct CoREST complexes act in a cell-type-specific manner

2019 ◽  
Author(s):  
Igor Mačinković ◽  
Ina Theofel ◽  
Tim Hundertmark ◽  
Kristina Kovač ◽  
Stephan Awe ◽  
...  
Keyword(s):  
Gene Expression ◽  
Germ Line ◽  
Protein Complexes ◽  
Specific Gene ◽  
S2 Cells ◽  
Cell Type ◽  
Specific Gene Expression ◽  
Genome Wide ◽  
A Cell ◽  
Cell Type Specific

Abstract CoREST has been identified as a subunit of several protein complexes that generate transcriptionally repressive chromatin structures during development. However, a comprehensive analysis of the CoREST interactome has not been carried out. We use proteomic approaches to define the interactomes of two dCoREST isoforms, dCoREST-L and dCoREST-M, in Drosophila. We identify three distinct histone deacetylase complexes built around a common dCoREST/dRPD3 core: A dLSD1/dCoREST complex, the LINT complex and a dG9a/dCoREST complex. The latter two complexes can incorporate both dCoREST isoforms. By contrast, the dLSD1/dCoREST complex exclusively assembles with the dCoREST-L isoform. Genome-wide studies show that the three dCoREST complexes associate with chromatin predominantly at promoters. Transcriptome analyses in S2 cells and testes reveal that different cell lineages utilize distinct dCoREST complexes to maintain cell-type-specific gene expression programmes: In macrophage-like S2 cells, LINT represses germ line-related genes whereas other dCoREST complexes are largely dispensable. By contrast, in testes, the dLSD1/dCoREST complex prevents transcription of germ line-inappropriate genes and is essential for spermatogenesis and fertility, whereas depletion of other dCoREST complexes has no effect. Our study uncovers three distinct dCoREST complexes that function in a lineage-restricted fashion to repress specific sets of genes thereby maintaining cell-type-specific gene expression programmes.

scholarly journals Genome-Wide Analysis of Cell Type-Specific Gene Transcription during Spore Formation in Clostridium difficile

PLoS Genetics ◽  
2013 ◽  
Vol 9 (10) ◽  
pp. e1003756 ◽  
Author(s):  
Laure Saujet ◽  
Fátima C. Pereira ◽  
Monica Serrano ◽  
Olga Soutourina ◽  
Marc Monot ◽  
...  
Keyword(s):  
Clostridium Difficile ◽  
Gene Transcription ◽  
Spore Formation ◽  
Specific Gene ◽  
Cell Type ◽  
Genome Wide Analysis ◽  
Genome Wide ◽  
Cell Type Specific

scholarly journals Cell-type specific and combinatorial usage of diverse transcription factors revealed by genome-wide binding studies in multiple human cells

2011 ◽  
Vol 22 (1) ◽  
pp. 9-24 ◽  
Author(s):  
B.-K. Lee ◽  
A. A. Bhinge ◽  
A. Battenhouse ◽  
R. M. McDaniell ◽  
Z. Liu ◽  
...  
Keyword(s):  
Transcription Factors ◽  
Human Cells ◽  
Cell Type ◽  
Binding Studies ◽  
Genome Wide ◽  
Cell Type Specific

scholarly journals Chromatin-enriched RNAs mark active and repressive cis-regulation: an analysis of nuclear RNA-seq

2019 ◽  
Author(s):  
Xiangying Sun ◽  
Zhezhen Wang ◽  
Carlos Perez-Cervantes ◽  
Alex Ruthenburg ◽  
Ivan Moskowitz ◽  
...  
Keyword(s):  
Gene Expression ◽  
Noncoding Rna ◽  
Molecular Mechanisms ◽  
Specific Gene ◽  
Rna Seq ◽  
Cell Type ◽  
Neighboring Gene ◽  
Cis Regulation ◽  
Nuclear Rna ◽  
Cell Type Specific

AbstractLong noncoding RNAs (lncRNAs) localize in the cell nucleus and influence gene expression through a variety of molecular mechanisms. RNA sequencing of two biochemical fractions of nuclei reveals a unique class of lncRNAs, termed chromatin-enriched nuclear RNAs (cheRNAs) that are tightly bound to chromatin and putatively function to cis-activate gene expression. Until now, a rigorous analytic pipeline for nuclear RNA-seq has been lacking. In this study, we survey four computational strategies for nuclear RNA-seq data analysis and show that a new pipeline, Tuxedo, outperforms other approaches. Tuxedo not only assembles a more complete transcriptome, but also identifies cheRNA with higher accuracy. We have used Tuxedo to analyze gold-standard K562 cell datasets and further characterize the genomic features of intergenic cheRNA (icheRNA) and their similarity to those of enhancer RNA (eRNA). Moreover, we quantify the transcriptional correlation of icheRNA and adjacent genes, and suggest that icheRNA may be the cis-acting transcriptional regulator that is more positively associated with neighboring gene expression than eRNA predicted by state-of-art method or CAGE signal. We also explore two novel genomic associations, suggesting cheRNA may have diverse functions. A possible new role of H3K9me3 modification coincident with icheRNA may be associated with active enhancer derived from ancient mobile elements, while a potential cis-repressive function of antisense cheRNA (as-cheRNA) is likely to be involved in transiently modulating cell type-specific cis-regulation.Author SummaryChromatin-enriched nuclear RNA (cheRNA) is a class of gene regulatory non-coding RNAs. CheRNA provides a powerful way to profile the nuclear transcriptional landscape, especially to profile the noncoding transcriptome. The computational framework presented here provides a reliable approach to identifying cheRNA, and for studying cell-type specific gene regulation. We found that intergenic cheRNA, including intergenic cheRNA with high levels of H3K9me3 (a mark associated with closed/repressed chromatin), may act as a transcriptional activator. In contrast, antisense cheRNA, which originates from the complementary strand of the protein-coding gene, may interact with diverse chromatin modulators to repress local transcription. With our new pipeline, one future challenge will be refining the functional mechanisms of these noncoding RNA classes through exploring their regulatory roles, which are involved in diverse molecular and cellular processes in human and other organisms.

scholarly journals Histone-Fold Domain Protein NF-Y Promotes Chromatin Accessibility for Cell Type-Specific Master Transcription Factors

2014 ◽  
Vol 55 (5) ◽  
pp. 708-722 ◽  
Author(s):  
Andrew J. Oldfield ◽  
Pengyi Yang ◽  
Amanda E. Conway ◽  
Senthilkumar Cinghu ◽  
Johannes M. Freudenberg ◽  
...  
Keyword(s):  
Transcription Factors ◽  
Chromatin Accessibility ◽  
Cell Type ◽  
Histone Fold ◽  
Histone Fold Domain ◽  
Cell Type Specific ◽  
Domain Protein

scholarly journals An interpretable bimodal neural network characterizes the sequence and preexisting chromatin predictors of induced TF binding

2019 ◽  
Author(s):  
Divyanshi Srivastava ◽  
Begüm Aydin ◽  
Esteban O. Mazzoni ◽  
Shaun Mahony
Keyword(s):  
Neural Network ◽  
Dna Binding ◽  
Dna Sequences ◽  
Binding Specificity ◽  
Chromatin Accessibility ◽  
Cell Type ◽  
Genome Wide ◽  
Binding Preference ◽  
Cell Type Specific ◽  
Insight Into

AbstractTranscription factor (TF) binding specificity is determined via a complex interplay between the TF’s DNA binding preference and cell type-specific chromatin environments. The chromatin features that correlate with TF binding in a given cell type have been well characterized. For instance, the binding sites for a majority of TFs display concurrent chromatin accessibility. However, concurrent chromatin features reflect the binding activities of the TF itself, and thus provide limited insight into how genome-wide TF-DNA binding patterns became established in the first place. To understand the determinants of TF binding specificity, we therefore need to examine how newly activated TFs interact with sequence and preexisting chromatin landscapes.Here, we investigate the sequence and preexisting chromatin predictors of TF-DNA binding by examining the genome-wide occupancy of TFs that have been induced in well-characterized chromatin environments. We develop Bichrom, a bimodal neural network that jointly models sequence and preexisting chromatin data to interpret the genome-wide binding patterns of induced TFs. We find that the preexisting chromatin landscape is a differential global predictor of TF-DNA binding; incorporating preexisting chromatin features improves our ability to explain the binding specificity of some TFs substantially, but not others. Furthermore, by analyzing site-level predictors, we show that TF binding in previously inaccessible chromatin tends to correspond to the presence of more favorable cognate DNA sequences. Bichrom thus provides a framework for modeling, interpreting, and visualizing the joint sequence and chromatin landscapes that determine TF-DNA binding dynamics.

scholarly journals Cell-type specific transcriptional adaptations of nucleus accumbens interneurons to amphetamine

2021 ◽  
Author(s):  
David A Gallegos ◽  
Melyssa Minto ◽  
Fang Liu ◽  
Mariah F Hazlett ◽  
S Aryana Yousefzadeh ◽  
...  
Keyword(s):  
Nucleus Accumbens ◽  
Molecular Mechanisms ◽  
Mutant Mouse ◽  
Chromatin Accessibility ◽  
Specific Gene ◽  
Cell Type ◽  
Transcriptional Program ◽  
Behavioral Sensitivity ◽  
Cell Type Specific ◽  
Insight Into

Parvalbumin-expressing (PV+) interneurons of the nucleus accumbens (NAc) play an essential role in the addictive-like behaviors induced by psychostimulant exposure. To identify molecular mechanisms of PV+ neuron plasticity, we isolated interneuron nuclei from the NAc of male and female mice following acute or repeated exposure to amphetamine (AMPH) and sequenced for cell type-specific RNA expression and chromatin accessibility. AMPH regulated the transcription of hundreds of genes in PV+ interneurons, and this program was largely distinct from that regulated in other NAc GABAergic neurons. Chromatin accessibility at enhancers predicted cell-type specific gene regulation, identifying transcriptional mechanisms of differential AMPH responses. Finally, we observed dysregulation of multiple PV-specific, AMPH-regulated genes in an Mecp2 mutant mouse strain that shows heightened behavioral sensitivity to psychostimulants, suggesting the functional importance of this transcriptional program. Together these data provide novel insight into the cell-type specific programs of transcriptional plasticity in NAc neurons that underlie addictive-like behaviors.

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