Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Dmrt2 and Hmx2 direct intercalated cell diversity in the mammalian kidney through antagonistic and supporting regulatory processes

ABSTRACT: Intercalated cells (ICs) in the mammalian kidney regulate circulatory pH through IC subtype restricted actions of bicarbonate transcporters: pH is elevated by Slc4a1 restricted to type A-ICs (A-ICs) and depressed by Slc26a4 in type B-IC (B-ICs). nonA-nonB-ICs (nA/nB-ICs) also produce Slc26a4 though their function is unclear. Though both nephron and ureteric progenitor lineages generate A-ICs, the former also generates nA/nB-ICs and the latter B-ICs. Lineage and subtype restricted transporter gene expression in the mouse and human kidney is preceded by expression of the transcriptional regulators Dmrt2/DMRT2 in A-ICs, and either, or both Hmx2/HMX2 and Hmx3/HMX3 in B- and nA/nB ICs. CRISPR/CAS9-directed removal of Dmrt2 and the linked Hmx2/Hmx3 genes resulted in IC-subtype switching. A-ICs adopted an Hmx2+/Slc26a4+ B-IC cell fate on Dmrt2 removal while B-ICs initiated a Dmrt2+/Slc4a1+ A-IC program on Hmx2/Hmx3 removal. Triple knockout of Dmrt2, Hmx2, and Hmx3 resulted in hybrid ICs expressing both Slc4a1 and Slc26a4. Thus, restricted expression of these regulators is essential for specifying IC subtypes. These data support a model in which mutually repressive interactions between Dmrt2 and Hmx2/3 establish distinct IC-identities and activity of these factors supports gene regulatory programs specific to each IC sub-type.

ORGANISM(S): Mus musculus

PROVIDER: GSE274904 | GEO | 2025/05/03

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

Dmrt2 and Hmx2 direct intercalated cell diversity in the mammalian kidney through antagonistic and supporting regulatory processes.

Project description:Intercalated cells (ICs) in the mammalian kidney regulate circulatory pH through IC subtype restricted actions of bicarbonate transcporters: pH is elevated by Slc4a1 restricted to type A-ICs (A-ICs) and depressed by Slc26a4 in type B-IC (B-ICs). nonA-nonB-ICs (nA/nB-ICs) also produce Slc26a4 though their function is unclear. Though both nephron and ureteric progenitor lineages generate A-ICs, the former also generates nA/nB-ICs and the latter B-ICs. Lineage and subtype restricted transporter gene expression in the mouse and human kidney is preceded by expression of the transcriptional regulators Dmrt2/DMRT2 in A-ICs, and either, or both Hmx2/HMX2 and Hmx3/HMX3 in B- and nA/nB ICs. CRISPR/CAS9-directed removal of Dmrt2 and the linked Hmx2/Hmx3 genes resulted in IC-subtype switching. A-ICs adopted an Hmx2+/Slc26a4+ B-IC cell fate on Dmrt2 removal while B-ICs initiated a Dmrt2+/Slc4a1+ A-IC program on Hmx2/Hmx3 removal. Triple knockout of Dmrt2, Hmx2, and Hmx3 resulted in hybrid ICs expressing both Slc4a1 and Slc26a4. Thus, restricted expression of these regulators is essential for specifying IC subtypes. These data support a model in which mutually repressive interactions between Dmrt2 and Hmx2/3 establish distinct IC-identities and activity of these factors supports gene regulatory programs specific to each IC sub-type.

2025-05-03 | GSE295893 | GEO

Aberrant expression of NKL homeobox genes HMX2 and HMX3 interferes with cell differentiation in acute myeloid leukemia

Project description:Our study illustrates the leukemic role of deregulated NKL homeobox genes HMX2 and HMX3 revealing molecular mechanisms of differentiation arrest in AML.Whole genome sequencing of EOL-1 identified two mutations in the regulatory upstream regions of HMX2/3 resulting in the generation of a novel ETS-site and transformation of a former NFkB-site into an SP1-site.

2020-09-23 | E-MTAB-9079 | biostudies-arrayexpress

Molecular Analyses of 10q hemizygous deletions and parents

Project description:We report on the analyses of four unrelated patients with de novo, overlapping, hemizygous deletions of the long arm of chromosome 10. These include two small terminal deletions (10q26.2 to 10qter), a larger terminal deletion (10q26.12 to 10qter), and an interstitial deletion (10q25.3q26.13). Single nucleotide polymorphism (SNP) studies (Illumina 550 K) established that these deletions resulted in the hemizygous loss of approximately 6.1, approximately 6.1, approximately 12.5, and approximately 7.0 Mb respectively. Additionally, these data establish that Patients 1, 2, and 3 share common, distal, hemizygous deleted regions of 6.09 Mb containing 37 RefSeq genes. Patients 3 and 4 share a 2.52 Mb deleted region corresponding to the proximal deleted region of Patient 3 and the distal deleted region of Patient 4. This common, hemizygous region contains 20 RefSeq genes including two H6 family homeobox genes (HMX2 and HMX3). Based on previous reports that Hmx2/Hmx3 knockout mice have vestibular anomalies, we propose that hemizygous deletions of HMX2 and HMX3 are responsible for the inner ear malformations observed from CT images, vestibular dysfunction, and congenital sensorineural hearing loss found in Patients 3 and 4. Four cases were identified as having hemizygous 10q deletions through g-banding. These were analyzed with SNP microarrays as well as parents (controls) for cases 1 and 4.

2009-07-01 | E-GEOD-11958 | biostudies-arrayexpress

Molecular Analyses of 10q hemizygous deletions and parents

2009-07-01 | GSE11958 | GEO

The role of quiescent thymic progenitors in TAL/LMO2-induced T-ALL chemotolerance

Project description:Relapse in T-cell acute lymphoblastic leukemia (T-ALL) may signify the persistence of leukemia-initiating cells (L-ICs). Ectopic TAL1/LMO expression defines the largest subset of T-ALL, but its role in leukemic transformation and its impact on relapse-driving L-ICs remain poorly understood. In TAL1/LMO mouse models, double negative-3 (DN3; CD4−CD8−CD25+CD44−) thymic progenitors harbored L-ICs. However, only a subset of DN3 leukemic cells exhibited L-IC activity, and studies linking L-ICs and chemotolerance are needed. To investigate L-IC heterogeneity, we used mouse models and applied single-cell RNA-sequencing and nucleosome labeling techniques in vivo. We identified a DN3 subpopulation with a cell cycle–restricted profile and heightened TAL1/LMO2 activity, that expressed genes associated with stemness and quiescence. This dormant DN3 subset progressively expanded throughout leukemogenesis, displaying intrinsic chemotolerance and enrichment in genes linked to minimal residual disease. Examination of TAL/LMO patient samples revealed a similar pattern in CD7+CD1a− thymic progenitors, previously recognized for their L-IC activity, demonstrating cell cycle restriction and chemotolerance. Our findings substantiate the emergence of dormant, chemotolerant L-ICs during leukemogenesis, and demonstrate that Tal1 and Lmo2 cooperate to promote DN3 quiescence during the transformation process. This study provides a deeper understanding of TAL1/LMO-induced T-ALL and its clinical implications in therapy failure.

2024-03-09 | GSE260948 | GEO

The role of quiescent thymic progenitors in TAL/LMO2-induced T-ALL chemotolerance

2024-03-02 | GSE260697 | GEO

IgG immunocomplexes sensitize human monocytes for inflammatory hyperactivity via transcriptomic and epigenetic reprogramming in Rheumatoid Arthritis

Project description:Prevalence of circulating immunocomplexes (ICs) strongly correlates with rheumatoid arthritis (RA) in humans. Deposits of IgG-ICs are abundant in affected joints of patients, yet molecular mechanisms for the pathogenic roles of such ICs are not fully understood. In this study, we present evidence that IgG-ICs precipitated from RA sera sensitized human monocytes for a long lasting inflammatory functional state, characterized by a strong TNF-a response to cellular proteins representing damage associated molecular patterns and microbe-derived pathogen-associated molecular patterns. Importantly, plate-coated human IgG (a mimic of deposited IC without Ag restriction) exhibited a similarly robust ability of monocyte sensitization in vitro. The plate-coated human IgG–induced functional programming is accompanied by transcriptomic and epigenetic modification of various inflammatory cytokines and negative regulator genes. Moreover, macrophages freshly isolated from synovia of patients with RA, but not sera-negative arthropathy, displayed a signature gene expression profile highly similar to that of IC-sensitized human monocytes, indicative of historical priming events by IgG-ICs in vivo. Thus, the ability of IgG-ICs to drive sustainable functional sensitization/reprogramming of monocytes and macrophages toward inflammation may render them key players in the of RA.

2017-10-15 | GSE102728 | GEO

Lupus IgA1 autoantibodies synergize with IgG to enhance pDC responses to RNA-containing immune complexes

Project description:Autoantibodies to nuclear antigens are hallmarks for diagnosis of the autoimmune disease systemic lupus erythematosus (SLE) and they contribute to SLE pathogenesis. However, there remains a gap in our knowledge regarding how different isotypes of autoantibodies contribute to key disease processes, including the production of the critical type I interferon (IFN) cytokines by plasmacytoid dendritic cells (pDCs) in response to immune complexes (ICs). Here, we show that individuals with SLE have IgA autoantibodies against most nuclear antigens assessed, largely correlating with the amounts of IgG against the same antigen. We investigated whether IgA autoantibodies against a major SLE autoantigen, Smith ribonucleoproteins (Sm/RNPs), play a role in IC activation of pDCs. We found that pDCs express the IgA-specific Fc receptor, FcRI, and there was a striking ability of IgA1 isotype autoantibodies to synergize with IgG in RNA-containing ICs to generate robust pDC IFN responses. pDC responses to these ICs required both FcRI and FcRIIa, suggesting the most potent ICs for pDCs contained autoantibodies of both isotypes. Sm/RNP IC binding to and internalization by pDCs were greater when ICs contained both IgA1 and IgG. In addition, binding of Sm/RNP ICs generated with IgA1-sufficient serum correlated to pDC FcRI expression, but not FcRIIa expression. pDCs from individuals with SLE had higher binding of IgA1-containing ICs and higher expression of FcRI than pDCs from healthy control individuals, correlating with expression of IFN response genes. Taken together, our data indicate that IgA1 ANAs contribute to SLE pathology and warrant further investigation.

2023-10-19 | GSE242721 | GEO

Anti-GD2 antibodies conjugated to IL15 and IL21 mediate potent anti-tumor cytotoxicity against neuroblastoma

Project description:Half of the patients with high-risk neuroblastoma (NB) who receive GD2-targeted monoclonal antibody do not achieve long-term remissions. Recently, the antibody hu14.18 has been linked to interleukin (IL)2 (hu14.18-IL2) to enhance its efficacy and shown promising preclinical and clinical activity. We developed two new immunocytokines (ICs) by linking two other γc cytokines, IL15 and IL21, to hu14.18. The purpose of this study was to compare hu14.18-IL15 and -IL21 to hu14.18-IL2 in their ability to induce antibody-dependent cell-mediated cytotoxicity (ADCC) against NB. We assessed ADCC of hu14.18-IL15 and -IL2 (human cytokines, cross-reactive to mouse) against GD2low and GD2high NB cell lines in vitro. T-cell deficient mice with orthotopic patient-derived xenografts (PDXs) and immunocompetent mice with transplantable orthotopic NB were used to test all three ICs, including hu14.18-IL21 (murine IL21, not cross-reactive to human). Mechanistic studies were performed using single-cell RNA-sequencing (scRNA-seq). Hu14.18-IL15 and hu14.18-IL2 mediated equivalent in vitro ADCC by human NK cells. When combined with chemotherapy, all three ICs similarly controlled the growth of PDXs in nude mice with murine NK effector cells. However, hu14.18-IL15 and -IL21 outperformed hu14.18-IL2 in immunocompetent mice with syngeneic NB, inducing complete tumor regressions and extending survival. scRNA-seq data revealed an increase in CD8+ T cells and M1 tumor-associated macrophages and decreased regulatory T cells and myeloid-derived suppressor cells in the tumor microenvironment. Hu14.18-IL15 and Hu14.18-IL21 exhibit robust preclinical activity, warranting further consideration for clinical testing in patients with GD2-expressing NB.

2022-09-01 | GSE206628 | GEO

A proteomics-based method for identifying antigens within immune complexes

Project description:A novel approach to recover and identify immune complexes (ICs) was developed using size exclusion chromatography (SEC) and affinity chromatography on immunoglobulin binding columns (HiTrap Protein G). The purification process was monitored by 1D SDS-PAGE, protein staining, Western blotting and, finally, liquid chromatography tandem mass spectrometry (LC MS/MS) was used to identify the recovered antigens. This approach was applied to serum with artificially created immune complexes (ICs) comprising vaccine antigen (influenza) and antibody, which led to recovery and identification of influenza peptides within the recovered ICs. This approach was compared with the established method for IC detection and recovery, polyethylene glycol (PEG) precipitation, followed by LC MS/MS. Both approaches successfully enabled capture, recovery and characterization of immunoglobulins and influenza antigen(s) in complex with the immunoglobulins. However, PEG precipitation has the advantage of simplicity and is more suited for large scale studies.

2021-01-04 | PXD021575 | Pride

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

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