Previous study demonstrated that HDAC3 has a critical role in MM proliferation; however, the underlying mechanism has not yet been elucidated. We identify that HDAC3 inhibition targets DNMT1 through dual regulations. We demonstrate that knockdown of DNMT1 leads to apoptosis and significant growth inhibition in myeloma cells. HDAC3 inhibition by gene silencing or HDAC3 selective inhibitor BG45 downregulates an oncoprotein c-Myc through its acetylation. c-Myc directly regulates DNMT1 expression at its enhancer region. Furthermore, HDAC3 directly regulates the stability of DNMT1 protein through its acetylation. Pharmaceutical inhibition of HDAC3 and DNMT1 synergistically induce MM growth inhibition in in vitro and in vivo settings.
HDAC3 regulates DNMT1 expression in multiple myeloma: therapeutic implications.
Cell line
View SamplesFoxp3+ T-regulatory cells (Tregs) are key to immune homeostasis such that their diminished numbers or function can cause autoimmunity and allograft rejection. Foxp3+ Tregs express histone/protein deacetylases (HDACs) that regulate chromatin remodeling, gene expression and protein function. Pan-HDAC inhibitors developed for oncology enhance Treg production and suppression but have limited non-oncologic applications given their broad effects. We show, using HDAC6-deficient mice and WT mice treated with HDAC6-specific inhibitors, that HDAC6 inhibition promotes Treg suppressive activity in models of inflammation and autoimmunity, including multiple forms of experimental colitis and fully MHC-incompatible cardiac allograft rejection. Many of the beneficial effects of HDAC6 targeting are also achieved by inhibition of the HDAC6-regulated protein, HSP90. Hence, selective targeting of a single HDAC isoform, HDAC6, or its downstream target, HSP90, can promote Treg-dependent suppression of autoimmunity and transplant rejection.
Histone deacetylase 6 and heat shock protein 90 control the functions of Foxp3(+) T-regulatory cells.
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Chemical genetic strategy identifies histone deacetylase 1 (HDAC1) and HDAC2 as therapeutic targets in sickle cell disease.
Specimen part, Treatment
View SamplesGene expression profiling was performed on primary human erythroid progenitor cells expressing a control shRNA (luciferase), two different HDAC1 shRNAs, and two different HDAC2 shRNAs.
Chemical genetic strategy identifies histone deacetylase 1 (HDAC1) and HDAC2 as therapeutic targets in sickle cell disease.
Specimen part
View SamplesGene expression profiling was performed on primary human erythroid progenitor cells left untreated or treated with 2uM NK57 for 3 days.
Chemical genetic strategy identifies histone deacetylase 1 (HDAC1) and HDAC2 as therapeutic targets in sickle cell disease.
Specimen part, Treatment
View SamplesGene expression profiling was performed on primary human erythroid progenitor cells left untreated or treated with 0.5uM SAHA.
Chemical genetic strategy identifies histone deacetylase 1 (HDAC1) and HDAC2 as therapeutic targets in sickle cell disease.
Specimen part, Treatment
View SamplesHere we report the gene expression profile of in vitro cultured human endometrial stromal cells treated with siRNA targeting FOXO1 piror to eutherian differentiation media exposure. The eutherian differentiation media contains cyclic AMP (cAMP) analogue 8-Br-cAMP and the progesterone (P4) analogue medroxyprogesterone acetate (MPA). Overall design: RNA-seq on decidualizing human endometrial stromal cells treated with siRNA targeting FOXO1.
The mammalian decidual cell evolved from a cellular stress response.
Specimen part, Treatment, Subject
View SamplesThe NEWEST (Neoadjuvant Endocrine Therapy for Women with Estrogen-Sensitive Tumours) trial compared the clinical and biological activity of fulvestrant 500 mg vs 250 mg in the neoadjuvant setting. In this multi-centre phase II study, post-menopausal women with operable, locally advanced (T2, 3, 4b; N0-3; M0) ER-positive breast tumours were randomised to receive neoadjuvant treatment with either dose of fulvestrant for 16 weeks before surgery.
Development and validation of a gene expression score that predicts response to fulvestrant in breast cancer patients.
Sex
View SamplesOrganismal function is, to a great extent, determined by interactions among their fundamental building blocks, the cells. In?this work, we studied the cell-cell interactome of fetal placental trophoblast cells and maternal endometrial stromal cells, using single-cell transcriptomics. The placental interface mediates the interaction between two semiallogenic individuals, the mother and the fetus, and is thus the epitome of cell interactions. To study these, we inferred the cell-cell interactome? by assessing the gene expression of receptor-ligand pairs across cell types. Moreover, we find that the expression of G-protein coupled receptors is highly cell-type?specific, implying that ligand-receptor profiles could be a reliable tool for cell type identification. Furthermore, we find that uterine decidual cells represent a cell-cell interaction hub with a relatively large?number of potential incoming and outgoing signals. Decidual cells differentiate from their precursors, the endometrial stromal fibroblasts, during uterine preparation for pregnancy. We show that decidualization (even in vitro) enhances the ability ?to communicate with the fetus, as most of the receptors and ligands up-regulated during decidualization have their counterpart expressed in trophoblast cells. Among the signals transmitted, growth factors and immune signals dominate, suggesting a delicate balance of enhancing and suppressive signals. Finally, this study provides a rich resource of gene ?expression profiles of term intravillous and extravillous trophoblasts, including the transcriptome of the multinucleated syncytiotrophoblast. Overall design: We sequenced mRNA from primary human endometrial stromal fibroblasts and in vitro human decidualized stromal fibroblasts.
Single-cell transcriptomics of the human placenta: inferring the cell communication network of the maternal-fetal interface.
Specimen part, Subject
View SamplesWe provide the tissue-level human placental transcriptomes from two term uncomplicated pregnancies. Tissue was collected at term C-section (no labor), from villous part of the placenta. Overall design: mRNA-seq of placenta from two term healthy pregnancies.
Single-cell transcriptomics of the human placenta: inferring the cell communication network of the maternal-fetal interface.
Specimen part, Subject
View Samples