NR1H4 [The Human Chemical-Genetic Interaction Map Project]

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======= NR1H4 =======


== Gene Information ==
  * **<color #00a2e8>Official Symbol</color>**: NR1H4
  * **<color #00a2e8>Official Name</color>**: nuclear receptor subfamily 1 group H member 4
  * **<color #00a2e8>Aliases and Previous Symbols</color>**: N/A
  * **<color #00a2e8>Entrez ID</color>**: [[https://www.ncbi.nlm.nih.gov/gene/?term=9971|9971]]
  * **<color #00a2e8>UniProt</color>**: [[https://www.uniprot.org/uniprot/Q96RI1|Q96RI1]]
  * **<color #00a2e8>Interactions</color>**: [[https://thebiogrid.org/search.php?search=NR1H4&organism=9606|BioGRID]]
  * **<color #00a2e8>PubMed articles</color>**: [[https://www.ncbi.nlm.nih.gov/pubmed/?term=gene%20NR1H4|Open PubMed]]
  * **<color #00a2e8>OMIM</color>**: [[https://omim.org/entry/603826|Open OMIM]]

== Function Summary ==
  * **<color #00a2e8>Entrez Summary</color>**:  This gene encodes a ligand-activated transcription factor that shares structural features in common with nuclear hormone receptor family members. This protein functions as a receptor for bile acids, and when bound to bile acids, binds to DNA and regulates the expression of genes involved in bile acid synthesis and transport. Alternatively spliced transcript variants encoding different isoforms have been described. [provided by RefSeq, Feb 2016]. 
  * **<color #00a2e8>UniProt Summary</color>**:  Ligand-activated transcription factor. Receptor for bile acids (BAs) such as chenodeoxycholic acid (CDCA), lithocholic acid, deoxycholic acid (DCA) and allocholic acid (ACA). Plays a essential role in BA homeostasis through the regulation of genes involved in BA synthesis, conjugation and enterohepatic circulation. Also regulates lipid and glucose homeostasis and is involved innate immune response (PubMed:10334992, PubMed:10334993, PubMed:21383957, PubMed:22820415). The FXR-RXR heterodimer binds predominantly to farnesoid X receptor response elements (FXREs) containing two inverted repeats of the consensus sequence 5'- AGGTCA-3' in which the monomers are spaced by 1 nucleotide (IR-1) but also to tandem repeat DR1 sites with lower affinity, and can be activated by either FXR or RXR-specific ligands. It is proposed that monomeric nuclear receptors such as NR5A2/LRH-1 bound to coregulatory nuclear responsive element (NRE) halfsites located in close proximity to FXREs modulate transcriptional activity (By similarity). In the liver activates transcription of the corepressor NR0B2 thereby indirectly inhibiting CYP7A1 and CYP8B1 (involved in BA synthesis) implicating at least in part histone demethylase KDM1A resulting in epigenomic repression, and SLC10A1/NTCP (involved in hepatic uptake of conjugated BAs). Activates transcription of the repressor MAFG (involved in regulation of BA synthesis) (By similarity). Activates transcription of SLC27A5/BACS and BAAT (involved in BA conjugation), ABCB11/BSEP (involved in bile salt export) by directly recruiting histone methyltransferase CARM1, and ABCC2/MRP2 (involved in secretion of conjugated BAs) and ABCB4 (involved in secretion of phosphatidylcholine in the small intestine) (PubMed:12754200, PubMed:15471871, PubMed:17895379). Activates transcription of SLC27A5/BACS and BAAT (involved in BA conjugation), ABCB11/BSEP (involved in bile salt export) by directly recruiting histone methyltransferase CARM1, and ABCC2/MRP2 (involved in secretion of conjugated BAs) and ABCB4 (involved in secretion of phosphatidylcholine in the small intestine) (PubMed:10514450, PubMed:15239098, PubMed:16269519). In the intestine activates FGF19 expression and secretion leading to hepatic CYP7A1 repression (PubMed:12815072, PubMed:19085950). The function also involves the coordinated induction of hepatic KLB/beta-klotho expression (By similarity). Regulates transcription of liver UGT2B4 and SULT2A1 involved in BA detoxification; binding to the UGT2B4 promoter seems to imply a monomeric transactivation independent of RXRA (PubMed:12806625, PubMed:16946559). Modulates lipid homeostasis by activating liver NR0B2/SHP-mediated repression of SREBF1 (involved in de novo lipogenesis), expression of PLTP (involved in HDL formation), SCARB1 (involved in HDL hepatic uptake), APOE, APOC1, APOC4, PPARA (involved in beta-oxidation of fatty acids), VLDLR and SDC1 (involved in the hepatic uptake of LDL and IDL remnants), and inhibiting expression of MTTP (involved in VLDL assembly (PubMed:12660231, PubMed:12554753, PubMed:15337761). Increases expression of APOC2 (promoting lipoprotein lipase activity implicated in triglyceride clearance) (PubMed:11579204). Transrepresses APOA1 involving a monomeric competition with NR2A1 for binding to a DR1 element (PubMed:11927623, PubMed:21804189). Also reduces triglyceride clearance by inhibiting expression of ANGPTL3 and APOC3 (both involved in inhibition of lipoprotein lipase) (PubMed:12891557). Involved in glucose homeostasis by modulating hepatic gluconeogenesis through activation of NR0B2/SHP-mediated repression of respective genes. Modulates glycogen synthesis (inducing phosphorylation of glycogen synthase kinase-3) (By similarity). Modulates glucose-stimulated insulin secretion and is involved in insulin resistance (PubMed:20447400). Involved in intestinal innate immunity. Plays a role in protecting the distal small intestine against bacterial overgrowth and preservation of the epithelial barrier (By similarity). Down- regulates inflammatory cytokine expression in several types of immune cells including macrophages and mononuclear cells (PubMed:21242261). Mediates trans-repression of TLR4-induced cytokine expression; the function seems to require its sumoylation and prevents N-CoR nuclear receptor corepressor clearance from target genes such as IL1B and NOS2 (PubMed:19864602). Involved in the TLR9-mediated protective mechanism in intestinal inflammation. Plays an anti-inflammatory role in liver inflammation; proposed to inhibit proinflammatory (but not antiapoptotic) NF-kappa-B signaling) (By similarity). {ECO:0000250|UniProtKB:Q60641, ECO:0000250|UniProtKB:Q62735, ECO:0000269|PubMed:10334992, ECO:0000269|PubMed:10334993, ECO:0000269|PubMed:10514450, ECO:0000269|PubMed:11579204, ECO:0000269|PubMed:11927623, ECO:0000269|PubMed:12554753, ECO:0000269|PubMed:12660231, ECO:0000269|PubMed:12718892, ECO:0000269|PubMed:12754200, ECO:0000269|PubMed:12806625, ECO:0000269|PubMed:12815072, ECO:0000269|PubMed:12891557, ECO:0000269|PubMed:14684751, ECO:0000269|PubMed:15239098, ECO:0000269|PubMed:15337761, ECO:0000269|PubMed:15471871, ECO:0000269|PubMed:16269519, ECO:0000269|PubMed:16946559, ECO:0000269|PubMed:17895379, ECO:0000269|PubMed:18621523, ECO:0000269|PubMed:19085950, ECO:0000269|PubMed:19410460, ECO:0000269|PubMed:19586769, ECO:0000269|PubMed:19864602, ECO:0000269|PubMed:20447400, ECO:0000269|PubMed:21242261, ECO:0000269|PubMed:21804189, ECO:0000269|PubMed:23928191, ECO:0000305|PubMed:21383957, ECO:0000305|PubMed:22820415}. Isoform 2: Promotes transcriptional activation of target genes ABCB11/BSEP (inducible by unconjugated CDCA, DCA and ACA), NR0B2/SHP (inducible by unconjugated CDCA DCA and ACA), SLC51B/OSTB (inducible by unconjugated CDCA and DCA) and FABP6/IBAP; not inducible by taurine- and glycine-amidated CDCA. {ECO:0000269|PubMed:23928191}. Isoform 4: Promotes transcriptional activation of target genes ABCB11/BSEP (inducible by unconjugated CDCA, ACA and DCA), NR0B2/SHP (inducible by unconjugated CDCA, ACA and DCA), SLC51B/OSTB (inducible by unconjugated CDCA and DCA) and FABP6/IBAP; most efficient isoform compared to isoforms 1 to 3; not inducible by taurine- and glycine-amidated CDCA. {ECO:0000269|PubMed:23928191, ECO:0000269|PubMed:26888176}.

<button type='primary' size='sm' modal='Pfam_Domains'>Pfam Domains</button>
<button type='primary' size='sm' modal='GO_terms'>GO Terms</button>


<modal id='Pfam_Domains' size='lg' title='Pfam Domains'>
|Hormone recep|
|zf-C4|
</modal>

<modal id='GO_terms' size='lg' title='GO Terms'>
|regulation of urea metabolic process|
|regulation of phosphatidic acid biosynthetic process|
|intracellular bile acid receptor signaling pathway|
|chenodeoxycholic acid binding|
|positive regulation of glutamate metabolic process|
|nitrogen catabolite activation of transcription|
|positive regulation of ammonia assimilation cycle|
|positive regulation of phosphatidic acid biosynthetic process|
|regulation of nitrogen cycle metabolic process|
|positive regulation of nitrogen utilization|
|regulation of ammonia assimilation cycle|
|nitrogen catabolite activation of transcription from RNA polymerase II promoter|
|bile acid receptor activity|
|interleukin-17 secretion|
|nitrogen catabolite regulation of transcription|
|nitrogen catabolite regulation of transcription from RNA polymerase II promoter|
|histone H3-R17 methylation|
|negative regulation of interferon-gamma secretion|
|bile acid signaling pathway|
|positive regulation of cellular amino acid metabolic process|
|regulation of glutamate metabolic process|
|regulation of nitrogen utilization|
|interleukin-17 production|
|negative regulation of bile acid biosynthetic process|
|negative regulation of bile acid metabolic process|
|positive regulation of adipose tissue development|
|negative regulation of monocyte chemotactic protein-1 production|
|regulation of glutamine family amino acid metabolic process|
|cellular triglyceride homeostasis|
|bile acid binding|
|negative regulation of tumor necrosis factor secretion|
|regulation of adipose tissue development|
|positive regulation of cellular amine metabolic process|
|regulation of bile acid biosynthetic process|
|regulation of interferon-gamma secretion|
|regulation of low-density lipoprotein particle clearance|
|regulation of bile acid metabolic process|
|positive regulation of phospholipid biosynthetic process|
|histone arginine methylation|
|fatty acid homeostasis|
|peptidyl-arginine methylation|
|regulation of monocyte chemotactic protein-1 production|
|toll-like receptor 9 signaling pathway|
|retinoid X receptor binding|
|regulation of phospholipid biosynthetic process|
|regulation of lipoprotein particle clearance|
|toll-like receptor 4 signaling pathway|
|negative regulation of chemokine production|
|nuclear receptor binding|
|negative regulation of tumor necrosis factor-mediated signaling pathway|
|positive regulation of insulin receptor signaling pathway|
|negative regulation of steroid biosynthetic process|
|negative regulation of interleukin-2 production|
|positive regulation of cellular response to insulin stimulus|
|negative regulation of steroid metabolic process|
|peptidyl-arginine modification|
|bile acid and bile salt transport|
|regulation of tumor necrosis factor secretion|
|nuclear euchromatin|
|negative regulation of interferon-gamma production|
|negative regulation of interleukin-1 production|
|positive regulation of insulin secretion involved in cellular response to glucose stimulus|
|triglyceride homeostasis|
|acylglycerol homeostasis|
|bile acid metabolic process|
|negative regulation of interleukin-6 production|
|negative regulation of I-kappaB kinase/NF-kappaB signaling|
|nuclear receptor activity|
|positive regulation of phospholipid metabolic process|
|cytokine secretion|
|negative regulation of lipid biosynthetic process|
|steroid hormone receptor activity|
|regulation of interleukin-2 production|
|cellular response to fatty acid|
|regulation of cholesterol metabolic process|
|regulation of insulin secretion involved in cellular response to glucose stimulus|
|anion homeostasis|
|regulation of tumor necrosis factor-mediated signaling pathway|
|negative regulation of tumor necrosis factor production|
|negative regulation of tumor necrosis factor superfamily cytokine production|
|negative regulation of cytokine-mediated signaling pathway|
|regulation of cellular amino acid metabolic process|
|regulation of insulin receptor signaling pathway|
|nuclear receptor transcription coactivator activity|
|negative regulation of response to cytokine stimulus|
|cellular response to nutrient|
|negative regulation of cytokine secretion|
|RNA polymerase II transcription factor complex|
|positive regulation of insulin secretion|
|regulation of cellular response to insulin stimulus|
|transcription regulatory region sequence-specific DNA binding|
|regulation of chemokine production|
|cholesterol homeostasis|
|positive regulation of lipid biosynthetic process|
|sterol homeostasis|
|regulation of cellular amine metabolic process|
|negative regulation of NF-kappaB transcription factor activity|
|negative regulation of lipid metabolic process|
|regulation of phospholipid metabolic process|
|response to fatty acid|
|regulation of steroid biosynthetic process|
|cellular glucose homeostasis|
|negative regulation of small molecule metabolic process|
|histone methylation|
|regulation of interleukin-1 production|
|positive regulation of peptide hormone secretion|
|toll-like receptor signaling pathway|
|regulation of interferon-gamma production|
|RNA polymerase II distal enhancer sequence-specific DNA binding|
|cell-cell junction assembly|
|regulation of steroid metabolic process|
|steroid hormone mediated signaling pathway|
|Notch signaling pathway|
|pattern recognition receptor signaling pathway|
|positive regulation of hormone secretion|
|negative regulation of protein secretion|
|lipid homeostasis|
|protein methylation|
|protein alkylation|
|monocarboxylic acid transport|
|negative regulation of inflammatory response|
|positive regulation of small molecule metabolic process|
|organic hydroxy compound transport|
|cell-cell junction organization|
|negative regulation of peptide secretion|
|regulation of interleukin-6 production|
|positive regulation of lipid metabolic process|
|regulation of tumor necrosis factor production|
|cytokine production|
|regulation of tumor necrosis factor superfamily cytokine production|
|protein secretion|
|establishment of protein localization to extracellular region|
|negative regulation of DNA-binding transcription factor activity|
|intracellular receptor signaling pathway|
|regulation of cytokine-mediated signaling pathway|
|protein localization to extracellular region|
|cell junction assembly|
|hormone-mediated signaling pathway|
|regulation of cellular ketone metabolic process|
|peptide secretion|
|regulation of response to cytokine stimulus|
|transcription initiation from RNA polymerase II promoter|
|regulation of insulin secretion|
|negative regulation of protein transport|
|cellular response to lipopolysaccharide|
|glucose homeostasis|
|negative regulation of establishment of protein localization|
|carbohydrate homeostasis|
|regulation of lipid biosynthetic process|
|cellular response to steroid hormone stimulus|
|cellular response to molecule of bacterial origin|
|negative regulation of secretion by cell|
|signaling receptor activity|
|regulation of cytokine secretion|
|negative regulation of defense response|
|cellular response to acid chemical|
|regulation of peptide hormone secretion|
|cell junction organization|
|response to nutrient|
|cellular response to biotic stimulus|
|DNA-templated transcription, initiation|
|negative regulation of secretion|
|cellular response to nutrient levels|
|innate immune response-activating signal transduction|
|regulation of I-kappaB kinase/NF-kappaB signaling|
|transcription corepressor activity|
|macromolecule methylation|
|activation of innate immune response|
|steroid metabolic process|
|cellular response to extracellular stimulus|
|regulation of hormone secretion|
|positive regulation of protein secretion|
|negative regulation of cytokine production|
|transcription coactivator activity|
|positive regulation of peptide secretion|
|carboxylic acid transport|
|organic acid transport|
|lipid transport|
|methylation|
|RNA polymerase II regulatory region sequence-specific DNA binding|
|response to lipopolysaccharide|
|lipid localization|
|response to molecule of bacterial origin|
|response to steroid hormone|
|defense response to bacterium|
|transcription factor binding|
|cellular response to external stimulus|
|regulation of inflammatory response|
|positive regulation of innate immune response|
|response to acid chemical|
|positive regulation of response to biotic stimulus|
|negative regulation of response to external stimulus|
|histone modification|
|covalent chromatin modification|
|regulation of lipid metabolic process|
|regulation of cellular amide metabolic process|
|positive regulation of secretion by cell|
|sequence-specific DNA binding|
|positive regulation of protein transport|
|regulation of small molecule metabolic process|
|regulation of DNA-binding transcription factor activity|
|positive regulation of secretion|
|DNA-binding transcription activator activity, RNA polymerase II-specific|
|regulation of innate immune response|
|organic hydroxy compound metabolic process|
|organic anion transport|
|positive regulation of establishment of protein localization|
|regulation of protein secretion|
|positive regulation of defense response|
|transcription by RNA polymerase II|
|negative regulation of transport|
|regulation of peptide secretion|
|inflammatory response|
|response to nutrient levels|
|negative regulation of intracellular signal transduction|
|positive regulation of multi-organism process|
|cellular response to lipid|
|regulation of response to biotic stimulus|
|monocarboxylic acid metabolic process|
|response to extracellular stimulus|
|regulation of hormone levels|
|cellular response to organic cyclic compound|
|immune response-activating signal transduction|
|anion transport|
|immune response-regulating signaling pathway|
|cellular response to organonitrogen compound|
|positive regulation of response to external stimulus|
|cellular response to hormone stimulus|
|activation of immune response|
|transcription, DNA-templated|
|nucleic acid-templated transcription|
|RNA biosynthetic process|
|cellular response to nitrogen compound|
|DNA-binding transcription factor activity|
|response to bacterium|
|regulation of cytokine production|
|chromatin organization|
|regulation of protein transport|
|regulation of peptide transport|
|cellular chemical homeostasis|
|regulation of establishment of protein localization|
|regulation of secretion by cell|
|regulation of defense response|
|innate immune response|
|regulation of multi-organism process|
|ion homeostasis|
|regulation of secretion|
|zinc ion binding|
|response to lipid|
|negative regulation of transcription by RNA polymerase II|
|positive regulation of immune response|
|peptidyl-amino acid modification|
|negative regulation of apoptotic process|
|cellular homeostasis|
|negative regulation of programmed cell death|
|carboxylic acid metabolic process|
|response to hormone|
|regulation of cellular localization|
|response to organic cyclic compound|
|defense response to other organism|
|positive regulation of transport|
|negative regulation of cell death|
|response to organonitrogen compound|
|oxoacid metabolic process|
|secretion by cell|
|organic acid metabolic process|
|regulation of protein localization|
|export from cell|
|cellular response to oxygen-containing compound|
|chromosome organization|
|response to nitrogen compound|
|regulation of response to external stimulus|
|nucleobase-containing compound biosynthetic process|
|chemical homeostasis|
|secretion|
|positive regulation of phosphate metabolic process|
|positive regulation of phosphorus metabolic process|
|negative regulation of molecular function|
|regulation of immune response|
|positive regulation of immune system process|
|heterocycle biosynthetic process|
|aromatic compound biosynthetic process|
|negative regulation of transcription, DNA-templated|
|negative regulation of multicellular organismal process|
|lipid metabolic process|
|positive regulation of transcription by RNA polymerase II|
|cellular response to endogenous stimulus|
|negative regulation of nucleic acid-templated transcription|
|negative regulation of RNA biosynthetic process|
|negative regulation of signal transduction|
|response to other organism|
|organic cyclic compound biosynthetic process|
|response to external biotic stimulus|
|response to biotic stimulus|
|negative regulation of RNA metabolic process|
|defense response|
|negative regulation of cell communication|
|negative regulation of signaling|
|positive regulation of developmental process|
|ion transport|
|negative regulation of cellular macromolecule biosynthetic process|
|negative regulation of nucleobase-containing compound metabolic process|
|negative regulation of macromolecule biosynthetic process|
|response to endogenous stimulus|
|regulation of response to stress|
|protein transport|
|negative regulation of cellular biosynthetic process|
|peptide transport|
|regulation of apoptotic process|
|positive regulation of transcription, DNA-templated|
|negative regulation of biosynthetic process|
|response to oxygen-containing compound|
|DNA-binding transcription factor activity, RNA polymerase II-specific|
|regulation of programmed cell death|
|amide transport|
|establishment of protein localization|
|negative regulation of response to stimulus|
|cellular nitrogen compound biosynthetic process|
|positive regulation of nucleic acid-templated transcription|
|positive regulation of RNA biosynthetic process|
|homeostatic process|
|positive regulation of signal transduction|
|regulation of immune system process|
|RNA metabolic process|
|regulation of cell death|
|cellular macromolecule biosynthetic process|
|negative regulation of gene expression|
|positive regulation of RNA metabolic process|
|positive regulation of multicellular organismal process|
|small molecule metabolic process|
|macromolecule biosynthetic process|
|regulation of phosphate metabolic process|
|regulation of phosphorus metabolic process|
|positive regulation of cell communication|
|positive regulation of signaling|
|regulation of intracellular signal transduction|
|nitrogen compound transport|
|regulation of transport|
|immune response|
|positive regulation of nucleobase-containing compound metabolic process|
|positive regulation of macromolecule biosynthetic process|
|positive regulation of cellular biosynthetic process|
|positive regulation of gene expression|
|gene expression|
|positive regulation of biosynthetic process|
</modal>
\\

 === CRISPR Data ===
<button type='primary' size='small' modal='Compound_Hit'>Compound Hit</button>
<button type='default' size='small' modal='Most_Correlated_Genes'>Most Correlated Genes in Chemogenomics</button>
<button type='primary' size='small' modal='Essential_Avana'>Tissues where Essential in the Avana Dataset (DepMap 20Q1)</button>

<modal id='Compound_Hit' size='lg' title='Compound Hit'>
^Screen^Score^
|[[:results:exp484|GSK-J5 1.5μM R08 exp484]]|1.72|
|[[:results:exp124|GSK343 3μM R03 exp124]]|1.9|
|[[:results:exp493|IL-3 9ng/ml R08 exp493]]|2.36|
</modal>

<modal id='Most_Correlated_Genes' size='lg' title='Most Correlated Genes in Chemogenomics'>
No correlation found to any other genes in chemogenomics.
</modal>

<modal id='Essential_Avana' size='lg' title='Tissues where Essential in the Avana Dataset (DepMap 20Q1)'>
Global Fraction of Cell Lines Where Essential: 1/739
^Tissue^Fraction Of Cell Lines Where Essential^
|1290807.0|0/1|
|909776.0|0/1|
|bile duct|0/28|
|blood|0/28|
|bone|0/26|
|breast|1/33|
|central nervous system|0/56|
|cervix|0/4|
|colorectal|0/17|
|esophagus|0/13|
|fibroblast|0/1|
|gastric|0/16|
|kidney|0/21|
|liver|0/20|
|lung|0/75|
|lymphocyte|0/16|
|ovary|0/26|
|pancreas|0/24|
|peripheral nervous system|0/16|
|plasma cell|0/15|
|prostate|0/1|
|skin|0/24|
|soft tissue|0/9|
|thyroid|0/2|
|upper aerodigestive|0/22|
|urinary tract|0/29|
|uterus|0/5|
</modal>

== Essentiality in NALM6  ==
    * **<color #00a2e8>Essentiality Rank</color>**: 8782
    * **<color #00a2e8>Expression level (log2 read counts)</color>**: -7.68 
<button type='primary' size='small' modal='Dist_expr'>Expression Distribution</button>
<modal id='Dist_expr' size='lg' title='NR1H4 Expression in NALM6 Cells: -7.68'>
{{:chemogenomics:nalm6 dist.png?nolink |}}
</modal>