scholarly journals TFAP2 paralogs pioneer chromatin access for MITF and directly inhibit genes associated with cell migration

2021 ◽  
Author(s):  
Colin Kenny ◽  
Ramile Dilshat ◽  
Hannah Seberg ◽  
Eric Van Otterloo ◽  
Gregory Bonde ◽  
...  
Keyword(s):  
Gene Expression ◽  
Transcription Factor ◽  
Cell Types ◽  
Chromatin Accessibility ◽  
Wild Type ◽  
Regulate Gene Expression ◽  
Enhancer Binding Protein ◽  
Pioneer Factors ◽  
Regulate Gene ◽  
Do So

Transcription factors in the Activating-enhancer-binding Protein 2 (TFAP2) family redundantly regulate gene expression in melanocytes and melanoma. Previous ChIP-seq experiments indicate that TFAP2A and Microphthalmia-associated Transcription Factor (MITF), a master regulator in these cell types, co-activate enhancers of genes promoting pigmentation. Evidence that TFAP2 paralogs can serve as pioneer factors supports the possibility that TFAP2 facilitates MITF binding at co-bound enhancers, although this model has not been tested. In addition, while MITF and TFAP2 paralogs both appear to repress genes that promote invasion, whether they do so by co-repressing enhancers is unknown. To address these questions we evaluated gene expression, chromatin accessibility, TFAP2A and MITF binding, and chromatin marks characteristic of active enhancers in SK-MEL-28 melanoma cells that were wild-type or deleted of the two TFAP2 paralogs with highest expression, TFAP2A and TFAP2C (i.e., TFAP2-KO cells). Integrated analyses revealed distinct subsets of enhancers bound by TFAP2A in WT cells that are inactivated and activated, respectively, in TFAP2-KO cells. At enhancers bound by both MITF and TFAP2A, MITF is generally lost in TFAP2A/TFAP2C double mutants, but not vice versa, implying TFAP2 pioneers chromatin access for MITF. There is a strong correlation between the sets of genes inhibited by MITF and TFAP2, although we did not find evidence that TFAP2 and MITF inhibit enhancers cooperatively. The findings imply that MITF and TFAP2 paralogs cooperatively affect the melanoma phenotype.

scholarly journals CoRE-ATAC: A deep learning model for the functional classification of regulatory elements from single cell and bulk ATAC-seq data

2020 ◽  
Author(s):  
Asa Thibodeau ◽  
Shubham Khetan ◽  
Alper Eroglu ◽  
Ryan Tewhey ◽  
Michael L. Stitzel ◽  
...  
Keyword(s):  
Gene Expression ◽  
Deep Learning ◽  
Immune Cells ◽  
Cell Types ◽  
Regulatory Elements ◽  
Chromatin Accessibility ◽  
Regulatory Function ◽  
Regulate Gene Expression ◽  
Regulatory Functions ◽  
Regulate Gene

AbstractCis-Regulatory elements (cis-REs) include promoters, enhancers, and insulators that regulate gene expression programs via binding of transcription factors. ATAC-seq technology effectively identifies active cis-REs in a given cell type (including from single cells) by mapping accessible chromatin at base-pair resolution. However, these maps are not immediately useful for inferring specific functions of cis-REs. For this purpose, we developed a deep learning framework (CoRE-ATAC) with novel data encoders that integrate DNA sequence (reference or personal genotypes) with ATAC-seq cut sites and read pileups. CoRE-ATAC was trained on 4 cell types (n=6 samples/replicates) and accurately predicted known cis-RE functions from 7 cell types (n=40 samples) that were not used in model training (mean average precision=0.80). CoRE-ATAC enhancer predictions from 19 human islet samples coincided with genetically modulated gain/loss of enhancer activity, which was confirmed by massively parallel reporter assays (MPRAs). Finally, CoRE-ATAC effectively inferred cis-RE function from aggregate single nucleus ATAC-seq (snATAC) data from human blood-derived immune cells that overlapped with known functional annotations in sorted immune cells, which established the efficacy of these models to study cis-RE functions of rare cells without the need for cell sorting. ATAC-seq maps from primary human cells reveal individual- and cell-specific variation in cis-RE activity. CoRE-ATAC increases the functional resolution of these maps, a critical step for studying regulatory disruptions behind diseases.Author SummaryNon-coding DNA sequences serve different functional roles to regulate gene expression. For these sequences to be active, they must be accessible for proteins and other factors to bind in order to carry out a specific regulatory function. Even so, mutations within these sequences or other regulatory events may modulate their activity or regulatory function. It is therefore critical that we identify these non-coding sequences and their specific regulatory function to fully understand how specific genes are regulated. Current sequencing technologies allow us to identify accessible sequences via chromatin accessibility maps from low cell numbers, enabling the study of clinical samples. However, determining the functional role associated with these sequences remains a challenge. Towards this goal, we harnessed the power of deep learning to unravel the intricacies of chromatin accessibility maps to infer their associated gene regulatory functions. We demonstrate that our method, CoRE-ATAC, can infer regulatory functions in diverse cell types, captures activity differences modulated by genetic mutations, and can be applied to accessibility maps of single cell clusters to infer regulatory functions of rare cell populations. These inferences will further our understanding of how genes are regulated and enable the study of these mechanisms as they relate to disease.

scholarly journals The temporal transcription factor E93 controls dynamic enhancer activity and chromatin accessibility during development

2019 ◽  
Author(s):  
Spencer L. Nystrom ◽  
Matthew J. Niederhuber ◽  
Daniel J. McKay
Keyword(s):  
Gene Expression ◽  
Transcription Factor ◽  
Developmental Time ◽  
Chromatin Accessibility ◽  
Wild Type ◽  
Spatial Cues ◽  
Enhancer Activity ◽  
Temporal Gene Expression ◽  
Developmental Program ◽  
Temporal Cues

ABSTRACTHow temporal cues combine with spatial inputs to control gene expression during development is poorly understood. Here, we test the hypothesis that the Drosophila transcription factor E93 controls temporal gene expression by regulating chromatin accessibility. Precocious expression of E93 early in wing development reveals that it can simultaneously activate and deactivate different target enhancers. Notably, the precocious patterns of enhancer activity resemble the wild-type patterns that occur later in development, suggesting that provision of E93 alters the competence of enhancers to respond to spatial cues. Genomic profiling reveals that precocious E93 expression is sufficient to regulate chromatin accessibility at a subset of its targets. These accessibility changes mimic those that normally occur later in development, indicating that precocious E93 accelerates the wild-type developmental program. Further, we find that target enhancers that do not respond to precocious E93 in early wings become responsive after a developmental transition, suggesting that parallel temporal pathways work alongside E93. These findings support a model wherein E93 expression functions as an instructive cue that defines a broad window of developmental time through control of chromatin accessibility.

scholarly journals Cohesin disrupts polycomb-dependent chromosome interactions

2019 ◽  
Author(s):  
JDP Rhodes ◽  
A Feldmann ◽  
B Hernández-Rodríguez ◽  
N Díaz ◽  
JM Brown ◽  
...  
Keyword(s):  
Gene Expression ◽  
Stem Cells ◽  
Embryonic Stem ◽  
Cell Types ◽  
Gene Repression ◽  
Chromosome Conformation ◽  
Regulate Gene Expression ◽  
Topologically Associating Domains ◽  
Chromosome Organisation ◽  
Regulate Gene

AbstractHow chromosome organisation is related to genome function remains poorly understood. Cohesin, loop-extrusion, and CTCF have been proposed to create structures called topologically associating domains (TADs) to regulate gene expression. Here, we examine chromosome conformation in embryonic stem cells lacking cohesin and find as in other cell types that cohesin is required to create TADs and regulate A/B compartmentalisation. However, in the absence of cohesin we identify a series of long-range chromosomal interactions that persist. These correspond to regions of the genome occupied by the polycomb repressive system, depend on PRC1, and we discover that cohesin counteracts these interactions. This disruptive activity is independent of CTCF and TADs, and regulates gene repression by the polycomb system. Therefore, in contrast to the proposal that cohesin creates structure in chromosomes, we discover a new role for cohesin in disrupting polycomb-dependent chromosome interactions to regulate gene expression.

scholarly journals Nkx3.1 Functions as Para-transcription Factor to Regulate Gene Expression and Cell Proliferation in Non-cell Autonomous Manner

2012 ◽  
Vol 287 (21) ◽  
pp. 17248-17256 ◽  
Author(s):  
Jian Zhou ◽  
Li Qin ◽  
Jean Ching-Yi Tien ◽  
Li Gao ◽  
Xian Chen ◽  
...  
Keyword(s):  
Gene Expression ◽  
Cell Proliferation ◽  
Transcription Factor ◽  
Regulate Gene Expression ◽  
Regulate Gene

scholarly journals A Single Mechanism of Biogenesis, Initiated and Directed by PIWI Proteins, Explains piRNA Production in Most Animals

2018 ◽  
Author(s):  
Ildar Gainetdinov ◽  
Cansu Colpan ◽  
Amena Arif ◽  
Katharine Cecchini ◽  
Phillip D. Zamore
Keyword(s):  
Gene Expression ◽  
Common Ancestor ◽  
Cell Types ◽  
Unified Model ◽  
Last Common Ancestor ◽  
Single Model ◽  
Regulate Gene Expression ◽  
Single Mechanism ◽  
Regulate Gene

SummaryIn animals, piRNAs guide PIWI-proteins to silence transposons and regulate gene expression. The mechanisms for making piRNAs have been proposed to differ among cell types, tissues, and animals. Our data instead suggest a single model that explains piRNA production in most animals. piRNAs initiate piRNA production by guiding PIWI proteins to slice precursor transcripts. Next, PIWI proteins direct the stepwise fragmentation of the sliced precursor transcripts, yielding tail-to-head strings of phased pre-piRNAs. Our analyses detect evidence for this piRNA biogenesis strategy across an evolutionarily broad range of animals including humans. Thus, PIWI proteins initiate and sustain piRNA biogenesis by the same mechanism in species whose last common ancestor predates the branching of most animal lineages. The unified model places PIWI-clade Argonautes at the center of piRNA biology and suggests that the ancestral animal—the Urmetazoan—used PIWI proteins both to generate piRNA guides and to execute piRNA function.

scholarly journals The Clock Protein CCA1 and the bZIP Transcription Factor HY5 Physically Interact to Regulate Gene Expression in Arabidopsis

2008 ◽  
Vol 1 (1) ◽  
pp. 58-67 ◽  
Author(s):  
Christos Andronis ◽  
Simon Barak ◽  
Stephen M. Knowles ◽  
Shoji Sugano ◽  
Elaine M. Tobin
Keyword(s):  
Gene Expression ◽  
Transcription Factor ◽  
Bzip Transcription Factor ◽  
Regulate Gene Expression ◽  
Clock Protein ◽  
Regulate Gene

scholarly journals Interaction of OIP5-AS1 with MEF2C mRNA promotes myogenic gene expression

2020 ◽  
Vol 48 (22) ◽  
pp. 12943-12956
Author(s):  
Jen-Hao Yang ◽  
Ming-Wen Chang ◽  
Poonam R Pandey ◽  
Dimitrios Tsitsipatis ◽  
Xiaoling Yang ◽  
...  
Keyword(s):  
Gene Expression ◽  
Transcription Factor ◽  
Muscle Regeneration ◽  
Muscle Development ◽  
Rna Binding ◽  
Myogenic Differentiation ◽  
Binding Protein ◽  
Rna Binding Protein ◽  
Regulate Gene Expression ◽  
Regulate Gene

Abstract Long noncoding (lnc)RNAs potently regulate gene expression programs in physiology and disease. Here, we describe a key function for lncRNA OIP5-AS1 in myogenesis, the process whereby myoblasts differentiate into myotubes during muscle development and muscle regeneration after injury. In human myoblasts, OIP5-AS1 levels increased robustly early in myogenesis, and its loss attenuated myogenic differentiation and potently reduced the levels of the myogenic transcription factor MEF2C. This effect relied upon the partial complementarity of OIP5-AS1 with MEF2C mRNA and the presence of HuR, an RNA-binding protein (RBP) with affinity for both transcripts. Remarkably, HuR binding to MEF2C mRNA, which stabilized MEF2C mRNA and increased MEF2C abundance, was lost after OIP5-AS1 silencing, suggesting that OIP5-AS1 might serve as a scaffold to enhance HuR binding to MEF2C mRNA, in turn increasing MEF2C production. These results highlight a mechanism whereby a lncRNA promotes myogenesis by enhancing the interaction of an RBP and a myogenic mRNA.

Transcription factor ThWRKY4 binds to a novel WLS motif and a RAV1A element in addition to the W-box to regulate gene expression

Plant Science ◽  
2017 ◽  
Vol 261 ◽  
pp. 38-49 ◽  
Author(s):  
Hongyun Xu ◽  
Xinxin Shi ◽  
Zhibo Wang ◽  
Caiqiu Gao ◽  
Chao Wang ◽  
...  
Keyword(s):  
Gene Expression ◽  
Transcription Factor ◽  
Regulate Gene Expression ◽  
Regulate Gene

The Gypsy Insulator of Drosophila Affects Chromatin Structure in a Directional Manner

Genetics ◽  
2001 ◽  
Vol 159 (4) ◽  
pp. 1649-1658
Author(s):  
Siquan Chen ◽  
Victor G Corces
Keyword(s):  
Gene Expression ◽  
Chromatin Structure ◽  
Protein A ◽  
Distal Region ◽  
Chromatin Accessibility ◽  
Chromatin Organization ◽  
Gypsy Insulator ◽  
Regulate Gene Expression ◽  
Hypersensitive Sites ◽  
Regulate Gene

Abstract Chromatin insulators are thought to regulate gene expression by establishing higher-order domains of chromatin organization, although the specific mechanisms by which these sequences affect enhancer-promoter interactions are not well understood. Here we show that the gypsy insulator of Drosophila can affect chromatin structure. The insulator itself contains several DNase I hypersensitive sites whose occurrence is dependent on the binding of the Suppressor of Hairy-wing [Su(Hw)] protein. The presence of the insulator in the 5′ region of the yellow gene increases the accessibility of the DNA to nucleases in the promoter-proximal, but not the promoter-distal, region. This increase in accessibility is not due to alterations in the primary chromatin fiber, because the number and position of the nucleosomes appears to be the same in the presence or absence of the insulator. Binding of the Su(Hw) protein to insulator DNA is not sufficient to induce changes in chromatin accessibility, and two domains of this protein, presumed to be involved in interactions with other insulator components, are essential for this effect. The presence of Modifier of mdg4 [Mod(mdg4)] protein, a second component of the gypsy insulator, is required to induce these alterations in chromatin accessibility. The results suggest that the gypsy insulator affects chromatin structure and offer insights into the mechanisms by which insulators affect enhancer-promoter interactions.

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