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 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 FIREcaller: Detecting Frequently Interacting Regions from Hi-C Data

2019 ◽  
Author(s):  
Cheynna Crowley ◽  
Yuchen Yang ◽  
Yunjiang Qiu ◽  
Benxia Hu ◽  
Armen Abnousi ◽  
...  
Keyword(s):  
Gene Regulation ◽  
Spatial Organization ◽  
R Package ◽  
Specific Gene ◽  
List Type ◽  
Cell Type ◽  
R Software ◽  
Computational Tools ◽  
Cell Type Specific ◽  
User Friendly

AbstractHi-C experiments have been widely adopted to study chromatin spatial organization, which plays an essential role in genome function. We have recently identified frequently interacting regions (FIREs) and found that they are closely associated with cell-type-specific gene regulation. However, computational tools for detecting FIREs from Hi-C data are still lacking. In this work, we present FIREcaller, a stand-alone, user-friendly R package for detecting FIREs from Hi-C data. FIREcaller takes raw Hi-C contact matrices as input, performs within-sample and cross-sample normalization, and outputs continuous FIRE scores, dichotomous FIREs, and super-FIREs. Applying FIREcaller to Hi-C data from various human tissues, we demonstrate that FIREs and super-FIREs identified, in a tissue-specific manner, are closely related to gene regulation, are enriched for enhancer-promoter (E-P) interactions, tend to overlap with regions exhibiting epigenomic signatures of cis-regulatory roles, and aid the interpretation or GWAS variants. The FIREcaller package is implemented in R and freely available at https://yunliweb.its.unc.edu/FIREcaller.Highlights– Frequently Interacting Regions (FIREs) can be used to identify tissue and cell-type-specific cis-regulatory regions.– An R software, FIREcaller, has been developed to identify FIREs and clustered FIREs into super-FIREs.

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 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.

scholarly journals Structural Changes in Transcriptional Regulatory Networks for Cell-type-specific Gene Expression During Hematopoiesis

2020 ◽  
Vol 14 ◽  
Keyword(s):  
Gene Expression ◽  
Transcription Factors ◽  
Regulatory Networks ◽  
Structural Changes ◽  
Specific Gene ◽  
Cell Type ◽  
Hematopoietic Stem ◽  
Specific Gene Expression ◽  
Transcriptional Regulatory ◽  
Cell Type Specific

Hematopoiesis is an extensively studied model system for cell differentiation. Cell-type-specific gene expression patterns are observed during hematopoiesis. Gene expression is governed by regulatory networks composed of cell-type-specific transcription factors. Resolving the transcriptional regulatory network for cell-type-specific gene expression provides a promising means of understanding the mechanisms underlying cell fate decisions. In this study, transcriptional regulatory networks in hematopoietic stem and progenitor cells were predicted based on gene expression profiles and distributions of transcription factor binding motifs in the promoter regions of cell-type-specific transcription factors. In particular, structural changes that occur when pluripotent stem cells progress to lineage-committed progenitors were evaluated. Marked changes in the regulatory circuit of transcription throughout the differentiation process could be elucidated by network analysis. Modular structures were a frequently described feature of biological networks observed in estimated networks. Within a module, most transcription factors were found to be regulated by a small number of regulators acting as downstream targets. Certain regulators within these modules coincide with known key regulators of hematopoietic cell differentiation. In addition to the modular structure, a twolayered structure was clearly observed in progenitor regulatory networks. Transcription factors could be distinctly divided into regulators within the regulatory layer and into targets in the output layer according to their degree of distribution. The restriction of mutual regulation between transcription factors was remarkable in that it allowed for alterations in network structures between hematopoietic stem cells and progenitors. Thus, using this approach, the relationships among transcription factors could be revealed by a reduction in mutual regulation to form a modular structure within the regulatory network

scholarly journals Identification of universal and cell type specific p53 DNA binding

2017 ◽  
Author(s):  
Antonina Hafner ◽  
Lyubov Kublo ◽  
Galit Lahav ◽  
Jacob Stewart-Ornstein
Keyword(s):  
Cell Lines ◽  
Binding Sites ◽  
Epithelial To Mesenchymal Transition ◽  
Chromatin Accessibility ◽  
Specific Gene ◽  
Cell Type ◽  
Cell Type Specificity ◽  
Mesenchymal Transition ◽  
Cell Type Specific ◽  
Meta Analyses

AbstractThe tumor suppressor p53 is a major regulator of the DNA damage response and has been suggested to selectively bind and activate cell type specific gene expression programs, however recent studies and meta-analyses of genomic data propose largely uniform, and condition independent, p53 binding. To systematically assess the cell type specificity of p53, we measured its association with DNA in 12 p53 wild-type cell lines, from a range of epithelial linages, in response to ionizing radiation. We found that the majority of bound sites were occupied across all cell lines, however we also identified a subset of binding sites that were specific to one or a few cell lines. Unlike the shared p53-bound genome, which was not dependent on chromatin accessibility, the association of p53 with these atypical binding sites was well explained by chromatin accessibility and could be modulated by forcing cell state changes such as the epithelial-to-mesenchymal transition. These results position p53 as having both universal and cell type specific regulatory programs that have different regulators and dependence on chromatin state.

scholarly journals Cell-type specific effects of genetic variation on chromatin accessibility during human neuronal differentiation

2020 ◽  
Author(s):  
Dan Liang ◽  
Angela L. Elwell ◽  
Nil Aygün ◽  
Michael J. Lafferty ◽  
Oleh Krupa ◽  
...  
Keyword(s):  
Genetic Variation ◽  
Neural Progenitor Cells ◽  
Cortical Development ◽  
Regulatory Elements ◽  
Chromatin Accessibility ◽  
Regulatory Mechanisms ◽  
List Type ◽  
Cell Type ◽  
Specific Effects ◽  
Cell Type Specific

SummaryCommon genetic risk for neuropsychiatric disorders is enriched in regulatory elements active during cortical neurogenesis. However, the mechanisms mediating the effects of genetic variants on gene regulation are poorly understood. To determine the functional impact of common genetic variation on the non-coding genome longitudinally during human cortical development, we performed a chromatin accessibility quantitative trait loci (caQTL) analysis in neural progenitor cells and their differentiated neuronal progeny from 92 donors. We identified 8,111 caQTLs in progenitors and 3,676 caQTLs in neurons, with highly temporal, cell-type specific effects. A subset (∼20%) of caQTLs were also associated with changes in gene expression. Motif-disrupting alleles of transcriptional activators generally led to decreases in chromatin accessibility, whereas motif-disrupting alleles of repressors led to increases in chromatin accessibility. By integrating cell-type specific caQTLs and brain-relevant genome-wide association data, we were able to fine-map loci and identify regulatory mechanisms underlying non-coding neuropsychiatric disorder risk variants.HighlightsGenetic variation alters chromatin architecture during human cortical developmentGenetic effects on chromatin accessibility are highly cell-type specificAlleles disrupting TF motifs generally decrease accessibility, except for repressorscaQTLs facilitate fine-mapping and inference of regulatory mechanisms of GWAS loci

scholarly journals Single-cell multiomics: technologies and data analysis methods

2020 ◽  
Vol 52 (9) ◽  
pp. 1428-1442 ◽  
Author(s):  
Jeongwoo Lee ◽  
Do Young Hyeon ◽  
Daehee Hwang
Keyword(s):  
Single Cell ◽  
Cell Types ◽  
Chromatin Accessibility ◽  
Cell Isolation ◽  
Integrative Analysis ◽  
Specific Gene ◽  
Cell Type ◽  
Cellular Events ◽  
Single Cell Isolation ◽  
Cell Type Specific

Abstract Advances in single-cell isolation and barcoding technologies offer unprecedented opportunities to profile DNA, mRNA, and proteins at a single-cell resolution. Recently, bulk multiomics analyses, such as multidimensional genomic and proteogenomic analyses, have proven beneficial for obtaining a comprehensive understanding of cellular events. This benefit has facilitated the development of single-cell multiomics analysis, which enables cell type-specific gene regulation to be examined. The cardinal features of single-cell multiomics analysis include (1) technologies for single-cell isolation, barcoding, and sequencing to measure multiple types of molecules from individual cells and (2) the integrative analysis of molecules to characterize cell types and their functions regarding pathophysiological processes based on molecular signatures. Here, we summarize the technologies for single-cell multiomics analyses (mRNA-genome, mRNA-DNA methylation, mRNA-chromatin accessibility, and mRNA-protein) as well as the methods for the integrative analysis of single-cell multiomics data.

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