Dataset Information

TCL1A, a Novel Transcription Factor and a Coregulator of Nuclear Factor ?B p65: Single Nucleotide Polymorphism and Estrogen Dependence.

ABSTRACT: T-cell leukemia 1A (TCL1A) single-nucleotide polymorphisms (SNPs) have been associated with aromatase inhibitor-induced musculoskeletal adverse events. We previously demonstrated that TCL1A is inducible by estradiol (E₂) and plays a critical role in the regulation of cytokines, chemokines, and Toll-like receptors in a TCL1A SNP genotype and estrogen-dependent fashion. Furthermore, TCLIA SNP-dependent expression phenotypes can be "reversed" by exposure to selective estrogen receptor modulators such as 4-hydroxytamoxifen (4OH-TAM). The present study was designed to comprehensively characterize the role of TCL1A in transcriptional regulation across the genome by performing RNA sequencing (RNA-seq) and chromatin immunoprecipitation sequencing (ChIP-seq) assays with lymphoblastoid cell lines. RNA-seq identified 357 genes that were regulated in a TCL1A SNP- and E₂-dependent fashion with expression patterns that were 4OH-TAM reversible. ChIP-seq for the same cells identified 57 TCL1A binding sites that could be regulated by E₂ in a SNP-dependent fashion. Even more striking, nuclear factor-?B (NF-?B) p65 bound to those same DNA regions. In summary, TCL1A is a novel transcription factor with expression that is regulated in a SNP- and E₂-dependent fashion-a pattern of expression that can be reversed by 4OH-TAM. Integrated RNA-seq and ChIP-seq results suggest that TCL1A also acts as a transcriptional coregulator with NF-?B p65, an important immune system transcription factor.

SUBMITTER: Ho MF

PROVIDER: S-EPMC5954488 | biostudies-literature | 2018 Jun

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

TCL1A, a Novel Transcription Factor and a Coregulator of Nuclear Factor κB p65: Single Nucleotide Polymorphism and Estrogen Dependence.

Ho Ming-Fen MF Lummertz da Rocha Edroaldo E Zhang Cheng C Ingle James N JN Goss Paul E PE Shepherd Lois E LE Kubo Michiaki M Wang Liewei L Li Hu H Weinshilboum Richard M RM

The Journal of pharmacology and experimental therapeutics 20180328 3

T-cell leukemia 1A (TCL1A) single-nucleotide polymorphisms (SNPs) have been associated with aromatase inhibitor-induced musculoskeletal adverse events. We previously demonstrated that TCL1A is inducible by estradiol (E2) and plays a critical role in the regulation of cytokines, chemokines, and Toll-like receptors in a TCL1A SNP genotype and estrogen-dependent fashion. Furthermore, TCLIA SNP-dependent expression phenotypes can be "reversed" by exposure to selective ...[more]

PMID: 29592948

Similar Datasets

Project description:The role of NF-kappaB in the expression of inflammatory genes and its participation in the overall inflammatory process of chronic diseases and acute tissue injury are well established. We and others have demonstrated a critical involvement of poly(ADP-ribose) polymerase (PARP)-1 during inflammation, in part, through its relationship with NF-kappaB. However, the mechanism by which PARP-1 affects NF-kappaB activation has been elusive. In this study, we show that PARP-1 inhibition by gene knockout, knockdown, or pharmacologic blockade prevented p65 NF-kappaB nuclear translocation in smooth muscle cells upon TLR4 stimulation, NF-kappaB DNA-binding activity, and subsequent inducible NO synthase and ICAM-1 expression. Such defects were reversed by reconstitution of PARP-1 expression. PARP-1 was dispensable for LPS-induced IkappaBalpha phosphorylation and subsequent degradation but was required for p65 NF-kappaB phosphorylation. A perinuclear p65 NF-kappaB localization in LPS-treated PARP-1(-/-) cells was associated with an export rather an import defect. Indeed, whereas PARP-1 deficiency did not alter expression of importin alpha3 and importin alpha4 and their cytosolic localization, the cytosolic levels of exportin (Crm)-1 were increased. Crm1 inhibition promoted p65 NF-kappaB nuclear accumulation as well as reversed LPS-induced p65 NF-kappaB phosphorylation and inducible NO synthase and ICAM-1 expression. Interestingly, p65 NF-kappaB poly(ADP-ribosyl)ation decreased its interaction with Crm1 in vitro. Pharmacologic inhibition of PARP-1 increased p65 NF-kappaB-Crm1 interaction in LPS-treated smooth muscle cells. These results suggest that p65 NF-kappaB poly(ADP-ribosyl)ation may be a critical determinant for the interaction with Crm1 and its nuclear retention upon TLR4 stimulation. These results provide novel insights into the mechanism by which PARP-1 promotes NF-kappaB nuclear retention, which ultimately can influence NF-kappaB-dependent gene regulation.

Dataset Information

TCL1A, a Novel Transcription Factor and a Coregulator of Nuclear Factor ?B p65: Single Nucleotide Polymorphism and Estrogen Dependence.

Publications

<i>TCL1A</i>, a Novel Transcription Factor and a Coregulator of Nuclear Factor <i>κ</i>B p65: Single Nucleotide Polymorphism and Estrogen Dependence.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

Dataset Information

TCL1A, a Novel Transcription Factor and a Coregulator of Nuclear Factor ?B p65: Single Nucleotide Polymorphism and Estrogen Dependence.

Publications

&lt;i&gt;TCL1A&lt;/i&gt;, a Novel Transcription Factor and a Coregulator of Nuclear Factor &lt;i&gt;κ&lt;/i&gt;B p65: Single Nucleotide Polymorphism and Estrogen Dependence.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

<i>TCL1A</i>, a Novel Transcription Factor and a Coregulator of Nuclear Factor <i>κ</i>B p65: Single Nucleotide Polymorphism and Estrogen Dependence.