Project description:Dissection of catalytic and non-catalytic functions of Tet1 and Tet2. Transcriptome profiling of wild type, Tet1 catalytic mutants, Tet2 and Tet1/2 catalytic mutant catalytic during EpiLC differentiation.

2020-10-05 | E-MTAB-6797 | biostudies-arrayexpress

TET2 Regulates Mast Cell Differentiation and Proliferation through Catalytic and Non-catalytic Activities.

Project description:Dioxygenases of the TET family impact genome functions by converting 5-methylcytosine in DNA to 5-hydroxymethylcytosine (5hmC), but their contribution to differentiation and function of immune cells is still incompletely understood. Here, we identified TET2 as a crucial regulator of mast cell differentiation and proliferation. Specifically, mast cell differentiation was impaired in absence of TET2, a defect that could be however compensated or further exacerbated modulating the activity of other TET family members. Mechanistically, delayed mast cell differentiation was related to the dysregulated expression of C/EBP transcription factors. Vice versa, the marked increase in proliferation induced by the absence of TET2 could be rescued exclusively by the specific re-expression of TET2 itself, regardless of its enzymatic activity. Our data indicate that in absence of TET2, mast cell differentiation is largely under the control of compensatory mechanisms mediated by other TET family members, while proliferation is strictly dependent on TET2 expression.

2016-05-04 | GSE77844 | GEO

TET2 Regulates Mast Cell Differentiation and Proliferation through Catalytic and Non-catalytic Activities.

Project description:Dioxygenases of the TET family impact genome functions by converting 5-methylcytosine (5mC) in DNA to 5-hydroxymethylcytosine (5hmC). Here, we identified TET2 as a crucial regulator of mast cell differentiation and proliferation. In the absence of TET2, mast cells showed disrupted gene expression and altered genome-wide 5hmC deposition, especially at enhancers and in proximity of down-regulated genes. Impaired differentiation of Tet2-ablated cells could be compensated or further exacerbated by modulating the activity of other TET family members, and mechanistically it could be linked to the dysregulated expression of C/EBP family transcription factors. Conversely, the marked increase in proliferation induced by the loss of TET2 could be rescued exclusively by re-expression of wild-type or catalytically inactive TET2. Our data indicate that in the absence of TET2, mast cell differentiation is under the control of compensatory mechanisms mediated by other TET family members, while proliferation is strictly dependent on TET2 expression.

2016-05-04 | GSE79090 | GEO

TET2 Regulates Mast Cell Differentiation and Proliferation through Catalytic and Non-catalytic Activities.

Project description:Dioxygenases of the TET family impact genome functions by converting 5-methylcytosine in DNA to 5-hydroxymethylcytosine, but the individual contribution of the three family members to differentiation and function of myeloid cells is still incompletely understood. Using cells with a deletion in the Tet2 gene, we show that TET2 contributes to the regulation of mast cell differentiation, proliferation and effector functions. The differentiation defect observed in absence of TET2 could be however completely rescued or further exacerbated by modulating TET3 activity, and it was primarily linked to dysregulated expression of the C/EBP family of transcription factors. In contrast, hyper-proliferation induced by the lack of TET2 could not be modified by TET3. Together, our data indicate the existence of both overlapping and unique roles of individual TET proteins in regulating myeloid cell gene expression, proliferation and function.

2016-05-04 | GSE70815 | GEO

Non-catalytic functions of Tet2 are essential to regulate hematopoietic stem and progenitor cell homeostasis

Project description:To identify genes that are influenced by the catalytic and non-catalytic functions of Tet2 in hematopoietic stem and progenitor cells (HSPCs), we analyzed the gene expression profiles of Tet2 catalytic mutant (Tet2 Mut), Tet2 knockout (Tet2 KO) and wild-type HSPCs (or LSK, Lin–Sca-1+c-Kit+) and multi-potent progenitor (or MPP, Lin–) cells by RNA-seq.

2019-08-05 | GSE132090 | GEO

Cancer-associated ASXL1 mutations may act as gain-of-function mutations of the ASXL1-BAP1 complex

Project description:ASXL1 is the obligate regulatory subunit of a deubiquitinase complex whose catalytic subunit is BAP1. Heterozygous mutations of ASXL1 that result in premature truncations are frequent in myeloid leukemias and Bohring-Opitz syndrome. Here, we demonstrate that truncated ASXL1 proteins confer enhanced activity on the ASXL1-BAP1 complex. Stable expression of truncated, hyperactive ASXL1-BAP1 complexes in a hematopoietic precursor cell line resulted in global erasure of H2AK119Ub, striking depletion of H3K27me3, selective upregulation of a subset of genes whose promoters bore both H2AK119Ub and H3K4me3, and spontaneous differentiation to the mast cell lineage. These outcomes required the catalytic activity of BAP1, indicating these events were downstream consequences of H2AK119Ub erasure. In bone marrow precursors, truncated ASXL1-BAP1 expression cooperated with TET2 loss-of-function to increase differentiation to the myeloid lineage in vivo. We propose that pathological ASXL1 mutations confer gain-of-function on the ASXL-BAP1 complex. ChIP-Seq for H2AK119Ub, H3K4me3, H3K27me3 on EML cells. RNA-Seq on EML cells expressing ASXL1(1-479)+BAP1 and control.

2015-03-11 | E-GEOD-65555 | biostudies-arrayexpress