Limits...
Transcriptional and epigenetic regulation of T-helper lineage specification.

Tripathi SK, Lahesmaa R - Immunol. Rev. (2014)

Bottom Line: Combined with TCR stimuli, extracellular cytokine signals initiate the differentiation of naive CD4(+) T cells into specialized effector T-helper (Th) and regulatory T (Treg) cell subsets.The lineage specification and commitment process occurs through the combinatorial action of multiple transcription factors (TFs) and epigenetic mechanisms that drive lineage-specific gene expression programs.Moreover, we review current study linking immune disease-associated single-nucleotide polymorphisms with distal regulatory elements and their potential role in the disease etiology.

View Article: PubMed Central - PubMed

Affiliation: Turku Centre for Biotechnology, University of Turku and Åbo Akademi University, Turku, Finland; National Doctoral Programme in Informational and Structural Biology, Turku, Finland; Turku Doctoral Programme of Molecular Medicine (TuDMM), University of Turku, Turku, Finland.

Show MeSH
Regulatory single-nucleotide polymorphisms (SNPs) disrupt TF binding on a lineage-specificenhancer, which in turn results in loss of enhancer-mediated lineage-specific gene expressionprogram. SNPs identified in genome-wide association studies (GWAS) were found to be greatly enrichedin intergenic and intronic regions that are also likely sites for enhancer elements. SNPs candisrupt transcription factor (TF)-binding sites within enhancer regions. Here, we show a model whereunder normal state, TF binds to an enhancer element and allow binding for histone acetyltransferases, p300, and RNA polII, to initiate the transcription of target genes. A SNP localized inTF-binding site within the enhancer region can cause a disruption of TF binding and result inattenuation of recruitment of p300 and RNA polII to the enhancer and thereby lead to loss ofenhancer-mediated cell-specific gene expression.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4255756&req=5

fig05: Regulatory single-nucleotide polymorphisms (SNPs) disrupt TF binding on a lineage-specificenhancer, which in turn results in loss of enhancer-mediated lineage-specific gene expressionprogram. SNPs identified in genome-wide association studies (GWAS) were found to be greatly enrichedin intergenic and intronic regions that are also likely sites for enhancer elements. SNPs candisrupt transcription factor (TF)-binding sites within enhancer regions. Here, we show a model whereunder normal state, TF binds to an enhancer element and allow binding for histone acetyltransferases, p300, and RNA polII, to initiate the transcription of target genes. A SNP localized inTF-binding site within the enhancer region can cause a disruption of TF binding and result inattenuation of recruitment of p300 and RNA polII to the enhancer and thereby lead to loss ofenhancer-mediated cell-specific gene expression.

Mentions: We and others have integrated global epigenetic modifications data from distinct Th-cell lineageswith SNPs from public GWASs catalogs to determine whether these disease-associated SNPs areregulatory SNPs 11,23.The integrative analysis revealed that a number of SNPs were localized within the TF-binding motifson cis-regulatory modules (CRMs), including enhancers and promoters. Further, weexperimentally validated in Th cells a panel of these regulatory SNPs. Disruption of the TF-bindingsites over these CRMs resulted in changes in TF binding suggesting their role in regulating geneexpression 11. Thus, in Th cell context, SNPs withinlineage-specific TFBS on CRMs could cause dysregulation of lineage defining genes potentiallyresulting in modulation in Th cell-mediated immune responses (Fig. 5).


Transcriptional and epigenetic regulation of T-helper lineage specification.

Tripathi SK, Lahesmaa R - Immunol. Rev. (2014)

Regulatory single-nucleotide polymorphisms (SNPs) disrupt TF binding on a lineage-specificenhancer, which in turn results in loss of enhancer-mediated lineage-specific gene expressionprogram. SNPs identified in genome-wide association studies (GWAS) were found to be greatly enrichedin intergenic and intronic regions that are also likely sites for enhancer elements. SNPs candisrupt transcription factor (TF)-binding sites within enhancer regions. Here, we show a model whereunder normal state, TF binds to an enhancer element and allow binding for histone acetyltransferases, p300, and RNA polII, to initiate the transcription of target genes. A SNP localized inTF-binding site within the enhancer region can cause a disruption of TF binding and result inattenuation of recruitment of p300 and RNA polII to the enhancer and thereby lead to loss ofenhancer-mediated cell-specific gene expression.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4255756&req=5

fig05: Regulatory single-nucleotide polymorphisms (SNPs) disrupt TF binding on a lineage-specificenhancer, which in turn results in loss of enhancer-mediated lineage-specific gene expressionprogram. SNPs identified in genome-wide association studies (GWAS) were found to be greatly enrichedin intergenic and intronic regions that are also likely sites for enhancer elements. SNPs candisrupt transcription factor (TF)-binding sites within enhancer regions. Here, we show a model whereunder normal state, TF binds to an enhancer element and allow binding for histone acetyltransferases, p300, and RNA polII, to initiate the transcription of target genes. A SNP localized inTF-binding site within the enhancer region can cause a disruption of TF binding and result inattenuation of recruitment of p300 and RNA polII to the enhancer and thereby lead to loss ofenhancer-mediated cell-specific gene expression.
Mentions: We and others have integrated global epigenetic modifications data from distinct Th-cell lineageswith SNPs from public GWASs catalogs to determine whether these disease-associated SNPs areregulatory SNPs 11,23.The integrative analysis revealed that a number of SNPs were localized within the TF-binding motifson cis-regulatory modules (CRMs), including enhancers and promoters. Further, weexperimentally validated in Th cells a panel of these regulatory SNPs. Disruption of the TF-bindingsites over these CRMs resulted in changes in TF binding suggesting their role in regulating geneexpression 11. Thus, in Th cell context, SNPs withinlineage-specific TFBS on CRMs could cause dysregulation of lineage defining genes potentiallyresulting in modulation in Th cell-mediated immune responses (Fig. 5).

Bottom Line: Combined with TCR stimuli, extracellular cytokine signals initiate the differentiation of naive CD4(+) T cells into specialized effector T-helper (Th) and regulatory T (Treg) cell subsets.The lineage specification and commitment process occurs through the combinatorial action of multiple transcription factors (TFs) and epigenetic mechanisms that drive lineage-specific gene expression programs.Moreover, we review current study linking immune disease-associated single-nucleotide polymorphisms with distal regulatory elements and their potential role in the disease etiology.

View Article: PubMed Central - PubMed

Affiliation: Turku Centre for Biotechnology, University of Turku and Åbo Akademi University, Turku, Finland; National Doctoral Programme in Informational and Structural Biology, Turku, Finland; Turku Doctoral Programme of Molecular Medicine (TuDMM), University of Turku, Turku, Finland.

Show MeSH