Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Identification of LRH1-driven transcription factor circuitry for hepatocyte identity using cistromic analysis of super-enhancers

ABSTRACT: The gene expression circuitry that controls maintenance of normal liver physiology is poorly understood. Super-enhancers are known to contribute to mammalian cell identity. The injured liver loses normal functions, with concomitant decreased expression of key identity genes. Here, we identified core transcriptional regulators that are highly active in hepatocytes, using genome-wide analysis and hierarchical ordering of super-enhancer distribution. Using network analysis of super-enhancer-associated gene interactions and human GEO databases for liver diseases of various etiologies, we identified a super-enhancer-associated network, with core TFs of LRH1, HNF4a, PPARa and RXRa. In a mouse model, expression of core TFs was robustly inhibited by single or multiple challenge(s) with liver toxicant. Levels of LRH1 and PPARa were greatly diminished, whereas other TFs were moderately altered. In hepatocytes, overexpression of each core TF promoted induction of other core TFs, with recovery of hepatocyte identity. Particularly, LRH1 overexpression caused recovery of super-enhancer-associated signalling circuitry in liver-toxicant challenged mice, protecting against liver injury. Hepatic stellate cells showed a unique super-enhancer signature. Using cistromic analysis of gene expression, we identified a novel hepatocyte-specific transcriptional network, and found that LRH1 drives the positive feed-forward expression circuitry and expression of hepatocyte identity genes, improving our understanding of liver pathophysiology and identifying novel disease targets.

ORGANISM(S): Mus musculus

PROVIDER: GSE104302 | GEO | 2019/04/02

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Similar Datasets

Models of Human Core Transcriptional Regulatory Circuitries

Project description:A small set of core transcription factors (TFs) dominates control of the gene expression program in embryonic stem cells and other well-studied cellular models. These core TFs collectively regulate their own gene expression, thus forming an interconnected autoregulatory loop that can be considered the core transcriptional regulatory circuitry (CRC) for that cell type. There is limited knowledge of core TFs, and thus models of core regulatory circuitry, for most cell types. We recently discovered that genes encoding known core TFs forming CRCs are driven by super-enhancers, which provides an opportunity to systematically predict CRCs in poorly studied cell types through super-enhancer mapping. Here we use super-enhancer maps to generate CRC models for 75 human cell and tissue types. These core circuitry models should prove valuable for further investigating cell type-specific transcriptional regulation in healthy and diseased cells. ChIP-Seq for RUNX1 and GATA3 in Jurkat T cell acute lymphoblastic leukemia cells.

2015-12-18 | E-GEOD-76181 | biostudies-arrayexpress

Models of Human Core Transcriptional Regulatory Circuitries

2015-12-18 | GSE76181 | GEO

Occupancy profiling of HAND2, MEIS2 and TCF4 by CUT&Tag from Neuroblastoma cells

Project description:HAND2, MEIS2 and TCF4 are master transcription factors (TFs) in neuroblastoma and create an interconnected core regulatory circuitry (CRC) by directly occupying each other's and their own super-enhancers (SEs), which leads to high levels of each TF expression inside the CRC. Additionally, CRC TFs cooperatively co-occupy the same SE components, which promotes the expression of genes involved in cell identity and cell-type-specific activities. Super-enhancer-mediated CRC enriched at key oncogenes in neuroblastoma. In the present study, CUT&Tag (Cleavage Under Targets and Tagmentation) analysis was performed to explore the target of HAND2, MEIS2 and TCF4 in NB cells.

2024-05-06 | GSE234337 | GEO

Selective Disruption of Core Regulatory Transcription [ChIP-seq]

Project description:Activation of identity determining transcription factors (TFs), or core regulatory TFs, is governed by cell-type specific enhancers, an important subset of these being super enhancers (SEs). This mechanism is distinct from constitutive expression of housekeeping genes. The characterization of drug-like small molecules to selectively inhibit core regulatory circuitry is of high interest for treatment of cancers, which are addicted to core regulatory TF function at SEs. Surprisingly, we find histone deacetylases (HDAC) to be an indispensable component of SE-driven transcription. While histone acetylation is a marker for active genes, over accumulation of acetylation selectively halts core regulatory transcription. We show this conundrum may in part be explained by a SE-specific need for resetting histones to maintain SE boundaries, to facilitate enhancer-promoter looping and high levels of transcription.

2019-07-16 | GSE116344 | GEO

Selective Disruption of Core Regulatory Transcription [RNA-seq]

2019-05-29 | GSE121106 | GEO

Selective Disruption of Core Regulatory Transcription [single cell RNA-seq]

2019-08-27 | GSE121107 | GEO

Miswired enhancer logic drives translocation positive rhabdomyosarcoma

Project description:Core regularity transcription factors (CR TFs) define cell identity and lineage through an exquisitely precise and logical order during embryogenesis and development. These CR TFs regulated one another in three-dimensional space via distal enhancers that serve as logic gates embedded in their TF recognition sequences. Aberrant chromatin organization resulting in miswired circuitry of enhancer logic is a newly recognized feature in many cancers. Here, we report that PAX3-FOXO1 expression is driven by a translocated FOXO1 distal super enhancer (SE). ChIP-seq in tumors bearing rare PAX translocations implicate enhancer miswiring is a pervasive feature across all FP-RMS tumors. Therefore, our data reveal a mechanism of a translocated hijacked enhancer which disrupts the normal CR TF logic during skeletal muscle development (PAX3 to MYOD to MYOG), replacing it with an infinite loop logic that makes rhabdomyosarcoma cells unable to exit the undifferentiated proliferating stage.

2019-12-25 | GSE136799 | GEO

Polyomavirus and neuroendocrine regulomes converge to establish tumor dependencies

Project description:Merkel Cell carcinoma (MCC) is an aggressive neuroendocrine skin cancer often driven by Merkel cell polyomavirus T antigens. The epigenomic mechanisms driving MCC are poorly understood. We show that virus positive MCC (VP-MCC) super enhancer networks are committed to and controlled by lineage-specific neuroendocrine transcription factors (TFs) including LHX3, ISL1, ATOH1, INSM1, SOX2 and POU4F3. These VP-MCC TFs are central to core regulatory (CR) transcriptional circuitry, essential for growth, and co-bind enhancers with polyomavirus small T antigen. We establish that T antigen expression is directly regulated by LHX3 and ISL1, establishing a positive feedback autoregulatory circuitry for a neuroendocrine state.

2021-01-01 | GSE147406 | GEO

Super-enhancer Driven Core Regulatory Circuitry in MYCN-amplified Neuroblastoma

Project description:Super-enhancer Driven Core Regulatory Circuitry in MYCN-amplified Neuroblastoma

| PRJNA374524 | ENA

Fibrosis-activated transcriptional networks govern hepatocyte reprogramming and intra-hepatic communication in metabolic associated liver fibrosis

Project description:Liver fibrosis is a strong predictor of long-term mortality in patients with non-alcoholic fatty liver disease; yet the mechanisms underlying the progression from the comparatively benign fatty liver state to advanced non-alcoholic steatohepatitis (NASH) and liver fibrosis are incompletely under-stood. Using a cell type-resolved genomics approach, we show that comprehensive alterations in hepatocyte genomic and transcriptional settings during NASH progression, led to a partial loss of hepatocyte identity. The hepatocyte reprogramming was under tight cooperative control of a net-work of NASH-activated transcription factors (TFs), as exemplified by Elf3 and Glis2. Indeed, Elf3 and Glis2 controlled hepatocyte identity and fibrosis-dependent hepatokine genes targeting disease-associated hepatic stellate cell (HSC) gene programs. Thus, interconnected TF networks not only promoted hepatocyte dysfunction, but also directed the intra-hepatic crosstalk with HSCs necessary for NASH and fibrosis progression implying molecular “hub-centered” targeting strategies to be superior to existing mono-target approaches as currently used in NASH therapy.

2021-07-13 | PXD025691 | Pride

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data