scholarly journals H3K27 Acetylated Nucleosomes Facilitate HMGN Protein Localization at Regulatory Sites to Modulate The Interaction of Transcription Factors with Chromatin

2021 ◽  
Author(s):  
Shaofei Zhang ◽  
Yuri Postnikov ◽  
Alexei Lobanov ◽  
Takashi Furusawa ◽  
Tao Deng ◽  
...  
Keyword(s):  
Transcription Factors ◽  
Binding Proteins ◽  
Protein Localization ◽  
Specific Gene ◽  
Epigenetic Mark ◽  
Sequence Specificity ◽  
Cell Type ◽  
Regulatory Regions ◽  
Cell Type Specific ◽  
Regulatory Sites

Nucleosomes containing acetylated H3K27 are a major epigenetic mark of active chromatin and identify cell-type specific chromatin regulatory regions which serve as binding sites for transcription factors. Here we show that the ubiquitous nucleosome binding proteins HMGN1 and HMGN2 bind preferentially to H3K27ac nucleosomes at cell-type specific chromatin regulatory regions. HMGNs bind directly to the acetylated nucleosome; the H3K27ac residue and linker DNA facilitate the preferential binding of HMGNs to the modified nucleosomes. Loss of HMGNs increases the levels of H3K27me3 and the histone H1 occupancy at enhancers and promoters and alters the interaction of transcription factors with chromatin. These experiments indicate that the H3K27ac epigenetic mark affects the interaction of architectural protein with chromatin regulatory sites and provide insights into the molecular mechanism whereby ubiquitous chromatin binding proteins, which bind to chromatin without DNA sequence specificity, localize to regulatory chromatin and modulate cell-type specific gene expression.

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 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 H3K4 mono- and di-methyltransferase MLL4 is required for enhancer activation during cell differentiation

eLife ◽  
2013 ◽  
Vol 2 ◽  
Author(s):  
Ji-Eun Lee ◽  
Chaochen Wang ◽  
Shiliyang Xu ◽  
Young-Wook Cho ◽  
Lifeng Wang ◽  
...  
Keyword(s):  
Gene Expression ◽  
Transcription Factors ◽  
Cell Differentiation ◽  
Functional Redundancy ◽  
Model Systems ◽  
Specific Gene ◽  
Cell Type ◽  
Specific Gene Expression ◽  
Cell Type Specific ◽  
Differentiation Stage

Enhancers play a central role in cell-type-specific gene expression and are marked by H3K4me1/2. Active enhancers are further marked by H3K27ac. However, the methyltransferases responsible for H3K4me1/2 on enhancers remain elusive. Furthermore, how these enzymes function on enhancers to regulate cell-type-specific gene expression is unclear. In this study, we identify MLL4 (KMT2D) as a major mammalian H3K4 mono- and di-methyltransferase with partial functional redundancy with MLL3 (KMT2C). Using adipogenesis and myogenesis as model systems, we show that MLL4 exhibits cell-type- and differentiation-stage-specific genomic binding and is predominantly localized on enhancers. MLL4 co-localizes with lineage-determining transcription factors (TFs) on active enhancers during differentiation. Deletion of Mll4 markedly decreases H3K4me1/2, H3K27ac, Mediator and Polymerase II levels on enhancers and leads to severe defects in cell-type-specific gene expression and cell differentiation. Together, these findings identify MLL4 as a major mammalian H3K4 mono- and di-methyltransferase essential for enhancer activation during cell differentiation.

Cell-type-specific expression of the rat thyroperoxidase promoter indicates common mechanisms for thyroid-specific gene expression

1992 ◽  
Vol 12 (2) ◽  
pp. 576-588
Author(s):  
H Francis-Lang ◽  
M Price ◽  
M Polycarpou-Schwarz ◽  
R Di Lauro
Keyword(s):  
Dna Binding ◽  
Binding Proteins ◽  
Dna Binding Proteins ◽  
Proximal Region ◽  
Specific Gene ◽  
Cell Type ◽  
Specific Expression ◽  
Cell Type Specific Expression ◽  
Cell Type Specific ◽  
Rat Thyroid

A 420-bp fragment from the 5' end of the rat thyroperoxidase (TPO) gene was fused to a luciferase reporter and shown to direct cell-type-specific expression when transfected into rat thyroid FRTL-5 cells. Analysis of this DNA fragment revealed four regions of the promoter which interact with DNA-binding proteins present in FRTL-5 cells. Mutation of the DNA sequence within any of these regions reduced TPO promoter activity. The trans-acting factors binding to these sequences were compared with thyroid transcription factor 1 (TTF-1) and TTF-2, previously identified as transcriptional activators of another thyroid-specific gene, the thyroglobulin (Tg) gene. Purified TTF-1 binds to three regions of TPO which are protected by FRTL-5 proteins. Two of the binding sites overlap with recognition sites for other DNA-binding proteins. One TTF-1 site can also bind a protein (UFB) present in the nuclei of both expressing and nonexpressing cells. TTF-1 binding to the proximal region overlaps with that for a novel protein present in FRTL-5 cells which can also recognize the promoter-proximal region of Tg. Using a combination of techniques, the factor binding to the fourth TPO promoter site was shown to be TTF-2. We conclude, therefore, that the FRTL-5-specific expression of two thyroid restricted genes, encoding TPO and Tg, relies on a combination of the same trans-acting factors present in thyroid cells.

scholarly journals The Interplay Between Chromatin Architecture and Lineage-Specific Transcription Factors and the Regulation of Rag Gene Expression

2021 ◽  
Vol 12 ◽  
Author(s):  
Kazuko Miyazaki ◽  
Masaki Miyazaki
Keyword(s):  
Gene Expression ◽  
Transcription Factors ◽  
Cell Fate ◽  
Molecular Mechanisms ◽  
Current Knowledge ◽  
Specific Gene ◽  
Cell Type ◽  
Cell Fate Decisions ◽  
Chromatin Architecture ◽  
Cell Type Specific

Cell type-specific gene expression is driven through the interplay between lineage-specific transcription factors (TFs) and the chromatin architecture, such as topologically associating domains (TADs), and enhancer-promoter interactions. To elucidate the molecular mechanisms of the cell fate decisions and cell type-specific functions, it is important to understand the interplay between chromatin architectures and TFs. Among enhancers, super-enhancers (SEs) play key roles in establishing cell identity. Adaptive immunity depends on the RAG-mediated assembly of antigen recognition receptors. Hence, regulation of the Rag1 and Rag2 (Rag1/2) genes is a hallmark of adaptive lymphoid lineage commitment. Here, we review the current knowledge of 3D genome organization, SE formation, and Rag1/2 gene regulation during B cell and T cell differentiation.

scholarly journals Whole-body integration of gene expression and single-cell morphology

2020 ◽  
Author(s):  
Hernando M. Vergara ◽  
Constantin Pape ◽  
Kimberly I. Meechan ◽  
Valentyna Zinchenko ◽  
Christel Genoud ◽  
...  
Keyword(s):  
Gene Expression ◽  
Transcription Factors ◽  
High Resolution Electron Microscopy ◽  
Cell Types ◽  
Whole Body ◽  
Specific Gene ◽  
Entire Body ◽  
Cell Type ◽  
Cellular Expression ◽  
Cell Type Specific

SummaryAnimal bodies are composed of hundreds of cell types that differ in location, morphology, cytoarchitecture, and physiology. This is reflected by cell type-specific transcription factors and downstream effector genes implementing functional specialisation. Here, we establish and explore the link between cell type-specific gene expression and subcellular morphology for the entire body of the marine annelid Platynereis dumerilii. For this, we registered a whole-body cellular expression atlas to a high-resolution electron microscopy dataset, automatically segmented all cell somata and nuclei, and clustered the cells according to gene expression or morphological parameters. We show that collective gene expression most efficiently identifies spatially coherent groups of cells that match anatomical boundaries, which indicates that combinations of regionally expressed transcription factors specify tissue identity. We provide an integrated browser as a Fiji plugin to readily explore, analyse and visualise multimodal datasets with remote on-demand access to all available datasets.

Characterization of a novel Dictyostelium discoideum prespore-specific gene, PspB, reveals conserved regulatory sequences

Development ◽  
1994 ◽  
Vol 120 (6) ◽  
pp. 1601-1611 ◽  
Author(s):  
J.A. Powell-Coffman ◽  
R.A. Firtel
Keyword(s):  
Dictyostelium Discoideum ◽  
Molecular Mechanisms ◽  
Regulatory Element ◽  
Consensus Sequence ◽  
Specific Gene ◽  
Regulatory Sequences ◽  
Cell Type ◽  
Specific Expression ◽  
Regulatory Regions ◽  
Cell Type Specific

While Dictyostelium discoideum has been studied as a developmental system for decades, and many regulatory proteins have been cloned, the molecular mechanisms of cell-type-specific gene expression are poorly understood. In this paper we characterize a novel prespore gene, PspB, and undertake a comparative analysis of the regulatory regions in prespore-specific D. discoideum promoters. Sequence alignment of the PSPB gene product with other prespore-specific proteins identifies a conserved, repeated 12 amino acid cysteine-containing motif that may be involved in spore coat function or assembly. Analysis of the PspB promoter identifies two domains essential for developmentally induced promoter activity. The first region includes two CA-rich elements (CAEs) that we show to be functionally homologous to the cAMP-inducible elements previously identified in the SP60 (cotC) promoter. The PspB CAEs compete with the SP60 (cotC) CAEs for binding in vitro to a developmentally regulated nuclear activity. We identify this activity as G-box Binding Factor, a developmentally induced transcription factor. The PspB CAEs and adjacent nucleotides direct a very low level of prespore-enriched expression, but high levels of cell-type-specific expression requires a second promoter region: a 46-bp AT-rich sequence that does not resemble the CAEs or any other previously described late gene promoter elements. Comparison of the PspB AT element with regulatory regions of the SP60 (cotC), SP70 (cotB), and D19 (pspA) promoters reveals an extensive consensus sequence. We suggest that these AT-rich sequences may represent a common regulatory element (or elements) required for prespore gene activation.

scholarly journals Single nuclei chromatin profiles of ventral midbrain reveal cell identity transcription factors and cell type-specific gene regulatory variation

2020 ◽  
Author(s):  
Yujuan Gui ◽  
Kamil Grzyb ◽  
Mélanie H. Thomas ◽  
Jochen Ohnmacht ◽  
Pierre Garcia ◽  
...  
Keyword(s):  
Gene Expression ◽  
Transcription Factors ◽  
Cell Types ◽  
Mouse Strains ◽  
Specific Gene ◽  
Cell Type ◽  
Cell Identity ◽  
Regulatory Variation ◽  
Ventral Midbrain ◽  
Cell Type Specific

SUMMARYCell types in ventral midbrain are involved in diseases with variable genetic susceptibility such as Parkinson’s disease and schizophrenia. Many genetic variants affect regulatory regions and alter gene expression. We report 20 658 single nuclei chromatin accessibility profiles of ventral midbrain from two genetically and phenotypically distinct mouse strains. We distinguish ten cell types based on chromatin profiles and analysis of accessible regions controlling cell identity genes highlights cell type-specific key transcription factors. Regulatory variation segregating the mouse strains manifests more on transcriptome than chromatin level. However, cell type-level data reveals changes not captured at tissue level. To discover the scope and cell-type specificity of cis-acting variation in midbrain gene expression, we identify putative regulatory variants and show them to be enriched at differentially expressed loci. Finally, we find TCF7L2 to mediate trans-acting variation selectively in midbrain neurons. Our dataset provides an extensive resource to study gene regulation in mesencephalon.

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