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RELA haploinsufficiency manifesting as an atypical phenotype of Crohn’s disease

ABSTRACT: RELA haploinsufficiency manifesting as an atypical phenotype of Crohn’s disease

PROVIDER: PRJNA1268501 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR33723377.fastq.gz	Fastqsanger.gz
	SRR33723378.fastq.gz	Fastqsanger.gz
	SRR33723379.fastq.gz	Fastqsanger.gz
	SRR33723380.fastq.gz	Fastqsanger.gz

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RELA haploinsufficiency manifesting as an atypical phenotype of Crohn’s disease

Project description:Mutations in RELA, a key component of NF-κB signaling, are associated with dysregulated immune responses and inflammatory disorders. While immunodeficiency phenotypes associated with RELA haploinsufficiency have been reported, gastrointestinal manifestations remain poorly described. We aimed to characterize the clinical, genomic, and immunological features of a patient presenting with an atypical Crohn’s-like phenotype driven by RELA haploinsufficiency. We report a case of RELA haploinsufficiency in a 17-year-old male presenting with a Crohn’s-like phenotype, including pan-enteric inflammation, perianal disease, chronic mucocutaneous candidiasis, and lymphopenia. Whole exome sequencing revealed a heterozygous RELA missense variant (p.V196A), which might impaired RelA protein stability and function. Functional assays showed reduced NF-κB activity and protein expression. Immune profiling by CyTOF and scRNA-seq demonstrated Treg deficiency, high IFN-γ levels, a strong interferon signature, and aberrant activation of MAIT and cytotoxic CD4+ T cells with upregulation of IL23R and ADAM12.

2025-05-28 | GSE298194 | GEO

Human RELA haploinsufficiency results in autosomal dominant chronic mucocutaneous ulceration: the transcriptional profile of RelA haploinsufficient patients

Project description:The treatment of chronic mucocutaneous ulceration is challenging and only some patients respond selectively to inhibitors of tumor necrosis factor-alpha (TNF-a). TNF-a activates opposing pathways leading to caspase-8-mediated apoptosis as well as NF-kB-dependent cell survival. We investigated the etiology of autosomal dominant mucocutaneous ulceration in a family whose proband was dependent on anti-TNF-a therapy for sustained remission. A heterozygous mutation in RELA (NM_021975: c.559+1G>A), encoding the NF-kB subunit RelA (p65), segregated with the disease phenotype and resulted in RelA haploinsufficiency. The patients’ fibroblasts exhibited increased apoptosis in response to TNF-a, impaired NF-kB activation, and defective expression of NF-B-dependent anti-apoptotic genes. We show that Rela+/- mice have similarly impaired NF-kB activation, develop cutaneous ulceration from TNF-a exposure, and exhibit severe dextran sodium sulfate-induced colitis ameliorated by TNF-a inhibition. These findings demonstrate an essential contribution of biallelic RELA expression in protecting stromal cells from TNF-a-mediated cell death, thus delineating the mechanisms driving the effectiveness of TNF-a inhibition in this disease.

2017-05-09 | GSE98624 | GEO

TAB2 haploinsufficiency

Project description:TAB2 haploinsufficiency

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Role of RelA:CBP/p300 interaction on RelA-activated genes

Project description:A structure-function study of NF-kB subunit RelA and coactivator CBP/p300 interaction reveals the critical role of CBP/p300 in recruitment of RelA to its target promoter site. mRNA profiles of unstimulated or stimulated with TNFa rela-/- MEF reconstituted with RelA wild type or mutants were generated by deep sequencing, in duplicate

2013-09-09 | E-GEOD-46213 | biostudies-arrayexpress

Reconstituted Rela-/- MEF

Project description:Reconstituted Rela-/- MEF

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HDXMS comparison of NFkB (p50(39-350)/RelA(19-321) vs NFkB (p50(39-350)/RelA(19-549)

Project description:HDXMS comparison of NFkB (p50(39-350)/RelA(19-321) vs NFkB (p50(39-350)/RelA(19-549)

2022-04-12 | MSV000089247 | MassIVE

Reconstituted Rela-/- MEF

Project description:Protein deamidation is emerging as a post-translational modification that regulates protein function. The general role of protein deamidation is emerging asn fundamental to biological processes, yet remains is poorly understood. Here, we report that the rate-limiting enzyme of pyrimidine synthesis, a trifunctional enzyme containing activity of carbamoyl phosphate synthetase, aspartyl transcarbamoylase and dihydroorotase (CAD), deamidates the RelA subunit to inactivate NF-κB and promote glycolysis. Functional screening and identified CAD as a negative regulator of NF-κB activation, and biochemical analysis demonstrated that CAD deamidatesd RelA in vitro and in cellsto negate NF-κB activation. D eamidated RelA, though failed to activate the expression of NF-κB-dependent genes, thoughbut it up-regulated that of key glycolytic enzymes to promote glycolysis and cell proliferation. In proliferating cells, CAD is activated and catalyzes de novo pyrimidine synthesis to meet the metabolic need during S phase. CAD-mediated RelA deamidation and NF-κB inactivation and glycolytic gene expression paralleled in a cell cycle-dependent mannerdriven by CAD-mediated RelA deamidation are necessary for cell proliferation. In addition, CAD promoted glycolysis via deamidated RelA that up-regulated the expression of key glycolytic enzymes. Stratification of cancer cell lines by CAD-mediated RelA deamidation predicted their sensitivity to inhibitors of glycolytic enzymes, while a subset of mutations predisposed RelA to deamidation and promoted glycolysis to enable cell proliferation. This work describes a process of metabolic reprogramming enabled by CAD-mediated RelA deamidation that underpins cell proliferation and tumorigenesis.

2019-11-01 | GSE132871 | GEO

Identification of genes responsible for RelA-dependent proliferation arrest in HMEC conditionally expressing RelA

Project description:Immuno-histochemistry for RelA in breast tumors revealed a range of staining intensity and negative correlation between RelA levels and proliferation-index in estrogen receptor-positive tumors. Conditional expression of RelA arrested proliferation in primary mammary and fallopian tube epithelial cells. RelA dependent CDK4 downregulation was responsible for activating the G1/S checkpoint and cell cycle arrest. RelA target genes, including Interferon Response Factors (IRF), were up-regulated in the arrested cells. Among the IRFs, IRF1 expression correlates with RelA expression. Suppressing IRF1 restored CDK4 levels and rescued RelA-dependent proliferation arrest analogous to abrogating the G1/S checkpoint or restoring CDK4 levels. Apart from cyclins, regulation of CDK4 by the RelA-IRF1 transcriptional network controls proliferation of breast tumors and predicts sensitivity to a CDK4/6 inhibitor.

2015-09-26 | GSE65040 | GEO

Role of RelA:CBP/p300 interaction on RelA-activated genes

Project description:A structure-function study of NF-kB subunit RelA and coactivator CBP/p300 interaction reveals the critical role of CBP/p300 in recruitment of RelA to its target promoter site.

2013-09-09 | GSE46213 | GEO

CLIP-Seq experiment of Escherichia coli RelA wild type and RelA::C289Y mutant strains to identify specific RNAs that bind RelA

Project description:In this experiment, we carried out a global analysis of specific RNAs that are bound to the RelA protein. CLIP-Seq experiment was carried out with E. coli RelA wild type and RelA::C289Y mutant strains. Libraries were prepared and high throughput sequencing was done.

2021-09-16 | E-MTAB-10884 | biostudies-arrayexpress

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