scholarly journals Single nucleus multi-omics regulatory atlas of the murine pituitary

2020 ◽  
Author(s):  
Frederique Ruf-Zamojski ◽  
Zidong Zhang ◽  
Michel Zamojski ◽  
Gregory R. Smith ◽  
Natalia Mendelev ◽  
...  
Keyword(s):  
Latent Variable ◽  
Target Genes ◽  
Chromatin Accessibility ◽  
Specific Gene ◽  
Control Mechanisms ◽  
Cell Type ◽  
Single Nucleus ◽  
Cell Type Specific ◽  
Gene Regulatory

AbstractThe pituitary regulates growth, reproduction and other endocrine systems. To investigate transcriptional network epigenetic mechanisms, we generated paired single nucleus (sn) transcriptome and chromatin accessibility profiles in single mouse pituitaries and genome-wide sn methylation datasets. Our analysis provided insight into cell type epigenetics, regulatory circuit and gene control mechanisms. Latent variable pathway analysis detected corresponding transcriptome and chromatin accessibility programs showing both inter-sexual and inter-individual variation. Multi-omics analysis of gene regulatory networks identified cell type-specific regulons whose composition and function were shaped by the promoter accessibility state of target genes. Co-accessibility analysis comprehensively identified putative cis-regulatory regions, including a domain 17kb upstream of Fshb that overlapped the fertility-linked rs11031006 human polymorphism. In vitro CRISPR-deletion at this locus increased Fshb levels, supporting this domain’s inferred regulatory role. The sn pituitary multi-omics atlas (snpituitaryatlas.princeton.edu) is a public resource for elucidating cell type-specific gene regulatory mechanisms and principles of transcription circuit control.

scholarly journals The three-dimensional chromatin structure of the major human pancreatic cell types reveals lineage-specific regulatory architecture of T2D risk

2021 ◽  
Author(s):  
Su Chun ◽  
Long Gao ◽  
Catherine L May ◽  
James A Pippin ◽  
Keith Boehm ◽  
...  
Keyword(s):  
Single Cell ◽  
Target Genes ◽  
Genetic Diseases ◽  
Three Dimensional ◽  
Specific Gene ◽  
Cell Type ◽  
Pancreatic Cell ◽  
Regulatory Architecture ◽  
Cell Type Specific ◽  
Gene Regulatory

Three-dimensional (3D) chromatin organization maps help to dissect cell type-specific gene regulatory programs. Furthermore, 3D chromatin maps have contributed to elucidating the pathogenesis of complex genetic diseases by connecting distal regulatory regions and genetic risk variants to their respective target genes. To understand the cell type-specific regulatory architecture of diabetes risk, we generated transcriptomic and 3D epigenomic profiles of human pancreatic acinar, alpha, and beta cells using single-cell RNA-seq, single-cell ATAC-seq, and high-resolution Hi-C of sorted cells. Comparisons of these profiles revealed differential A/B (open/closed) chromatin compartmentalization, chromatin looping, and control of cell type-specific gene regulatory programs. We identified a total of 1,094 putative causal-variant-target-gene pairs at 129 type 2 diabetes GWAS signals using pancreatic 3D chromatin maps. We found that the connections between candidate causal variants and their putative target effector genes are cell-type stratified and emphasize previously underappreciated roles for alpha and acinar cells in diabetes pathogenesis

New insights into promoter–enhancer communication mechanisms revealed by dynamic single-molecule imaging

2021 ◽  
Author(s):  
Jieru Li ◽  
Alexandros Pertsinidis
Keyword(s):  
Gene Expression ◽  
Single Molecule ◽  
Target Genes ◽  
Regulatory Elements ◽  
Specific Gene ◽  
Single Molecule Imaging ◽  
Cell Type ◽  
Regulatory Information ◽  
Cell Type Specific ◽  
Target Promoters

Establishing cell-type-specific gene expression programs relies on the action of distal enhancers, cis-regulatory elements that can activate target genes over large genomic distances — up to Mega-bases away. How distal enhancers physically relay regulatory information to target promoters has remained a mystery. Here, we review the latest developments and insights into promoter–enhancer communication mechanisms revealed by live-cell, real-time single-molecule imaging approaches.

scholarly journals CT-FOCS: a novel method for inferring cell type-specific enhancer-promoter maps

2019 ◽  
Author(s):  
Tom Aharon Hait ◽  
Ran Elkon ◽  
Ron Shamir
Keyword(s):  
Gene Expression ◽  
Target Genes ◽  
Expression Patterns ◽  
Cell Types ◽  
Specific Gene ◽  
Cell Type ◽  
Chromatin Interactions ◽  
Cell Type Specific ◽  
Novel Method ◽  
Validation Scheme

AbstractSpatiotemporal gene expression patterns are governed to a large extent by enhancer elements, typically located distally from their target genes. Identification of enhancer-promoter (EP) links that are specific and functional in individual cell types is a key challenge in understanding gene regulation. We introduce CT-FOCS, a new statistical inference method that utilizes multiple replicates per cell type to infer cell type-specific EP links. Computationally predicted EP links are usually benchmarked against experimentally determined chromatin interactions measured by ChIA-PET and promoter-capture HiC techniques. We expand this validation scheme by using also loops that overlap in their anchor sites. In analyzing 1,366 samples from ENCODE, Roadmap epigenomics and FANTOM5, CT-FOCS inferred highly cell type-specific EP links more accurately than state-of-the-art methods. We illustrate how our inferred EP links drive cell type-specific gene expression and regulation.

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 scTenifoldKnk: a machine learning workflow performing virtual knockout experiments on single-cell gene regulatory networks

2021 ◽  
Author(s):  
Daniel Osorio ◽  
Yan Zhong ◽  
Guanxun Li ◽  
Qian Xu ◽  
Andrew E. Hillhouse ◽  
...  
Keyword(s):  
Machine Learning ◽  
Single Cell ◽  
Gene Function ◽  
Specific Gene ◽  
Cell Type ◽  
Cell Technology ◽  
Cell Type Specific ◽  
Gene Regulatory ◽  
The Impact ◽  
Cell Gene

Gene knockout (KO) experiments are a proven approach for studying gene function. A typical KO experiment usually involves the phenotypic characterization of KO organisms. The recent advent of single-cell technology has greatly boosted the resolution of cellular phenotyping, providing unprecedented insights into cell-type-specific gene function. However, the use of single-cell technology in large-scale, systematic KO experiments is prohibitive due to the vast resources required. Here we present scTenifoldKnk, a machine learning workflow that performs virtual KO experiments using single-cell RNA sequencing (scRNA-seq) data. scTenifoldKnk first uses data from wild-type (WT) samples to construct a single-cell gene regulatory network (scGRN). Then, a gene is knocked out from the constructed scGRN by setting weights of the gene's outward edges to zeros. ScTenifoldKnk then compares this "pseudo-KO" scGRN with the original scGRN to identify differentially regulated (DR) genes. These DR genes, also called virtual-KO perturbed genes, are used to assess the impact of the gene KO and reveal the gene's function in analyzed cells. Using existing data sets, we demonstrate that the scTenifoldKnk analysis recapitulates the main findings of three real-animal KO experiments and confirms the functions of genes underlying three Mendelian diseases. We show the power of scTenifoldKnk as a predictive method to successfully predict the outcomes of two KO experiments that involve intestinal enterocytes in Ahr-/- mice and pancreatic islet cells in Malat1-/- mice, respectively. Finally, we demonstrate the use of scTenifoldKnk to perform systematic KO analyses, in which a large number of genes are virtually deleted, allowing gene functions to be revealed in a cell type-specific manner.

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 IRIS3: integrated cell-type-specific regulon inference server from single-cell RNA-Seq

2020 ◽  
Vol 48 (W1) ◽  
pp. W275-W286 ◽  
Author(s):  
Anjun Ma ◽  
Cankun Wang ◽  
Yuzhou Chang ◽  
Faith H Brennan ◽  
Adam McDermaid ◽  
...  
Keyword(s):  
Single Cell ◽  
Target Genes ◽  
Complex Diseases ◽  
Specific Cell ◽  
Rna Seq ◽  
Cell Type ◽  
Specific Cell Type ◽  
Cell Type Specific ◽  
Gene Regulatory ◽  
Human And Mouse

Abstract A group of genes controlled as a unit, usually by the same repressor or activator gene, is known as a regulon. The ability to identify active regulons within a specific cell type, i.e., cell-type-specific regulons (CTSR), provides an extraordinary opportunity to pinpoint crucial regulators and target genes responsible for complex diseases. However, the identification of CTSRs from single-cell RNA-Seq (scRNA-Seq) data is computationally challenging. We introduce IRIS3, the first-of-its-kind web server for CTSR inference from scRNA-Seq data for human and mouse. IRIS3 is an easy-to-use server empowered by over 20 functionalities to support comprehensive interpretations and graphical visualizations of identified CTSRs. CTSR data can be used to reliably characterize and distinguish the corresponding cell type from others and can be combined with other computational or experimental analyses for biomedical studies. CTSRs can, therefore, aid in the discovery of major regulatory mechanisms and allow reliable constructions of global transcriptional regulation networks encoded in a specific cell type. The broader impact of IRIS3 includes, but is not limited to, investigation of complex diseases hierarchies and heterogeneity, causal gene regulatory network construction, and drug development. IRIS3 is freely accessible from https://bmbl.bmi.osumc.edu/iris3/ with no login requirement.

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