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The glucocorticoid receptor elicited proliferative response in human erythropoiesis is BCL11A-dependent

ABSTRACT: Prior evidence indicates that the erythroid cellular response to glucocorticoids (GC) has developmental specificity, namely, that developmentally more advanced cells that are undergoing or have undergone fetal to adult globin switching are more responsive to GC-induced expansion. To investigate the molecular underpinnings of this, we focused on the major developmental globin regulator BCL11A. We compared: a) levels of expression and nuclear content of BCL11A in adult erythroid cells upon GC stimulation; b) response to GC of CD34+ cells from patients with BCL11A microdeletions and reduced BCL11A expression, and; c) response to GC of two cellular models (HUDEP-2 and adult CD34+ cells) before and after reduction of BCL11A expression by shRNA. We observed that: a) GC-expanded erythroid cells from a large cohort of blood donors displayed amplified expression and nuclear accumulation of BCL11A; b) CD34+ cells from BCL11A microdeletion patients generated fewer erythroid cells when cultured with GC compared to their parents, while the erythroid expansion of the patients was similar to that of their parents in cultures without GC, and; c) adult CD34+ cells and HUDEP-2 cells with shRNA-depleted expression of BCL11A exhibit reduced expansion in response to GC. In addition, RNA-seq profiling of shRNA-BCL11A CD34+ cells cultured with and without GC was similar (very few differentially expressed genes), while GC-specific responses (differential expression of GILZ and of numerous additional genes) were observed only in controls cells with unperturbed BCL11A expression. These data indicate that BCL11A is an important participant of certain aspects of the stress pathway sustained by GC.

ORGANISM(S): Homo sapiens

PROVIDER: GSE274928 | GEO | 2024/09/01

REPOSITORIES: GEO

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Project description:MicroRNAs (miRNAs) are small non-coding RNAs (sncRNAs) crucial for post-transcriptional and translational regulation of cellular and developmental pathways. Study of miRNAs in erythropoiesis thus elucidates the process and facilitates diagnosis and therapy development for related disorders. Here, we used high-throughput DNA Nanoball small RNA sequencing to characterise sncRNAs, and in particular miRNAs, comprehensively in human erythroid cell cultures. Based on primary human peripheral-blood-derived CD34+ (hCD34+) cells and on two influential erythroid cell lines with adult and fetal expression patterns, HUDEP-2 and HUDEP-1, respectively, our study links differential expression (DE) to erythroid differentiation, cell type, and fetal and adult hemoglobin expression patterns. Sequencing results were validated by reverse-transcription quantitative PCR (RT-qPCR) of selected DE miRNAs (miR-451a, miR-182-5p, miR-146a-5p, miR-221-3p, miR-222-3p) and indicated overall common erythroid differentiation signatures in primary cells and cell lines, in terminal stages of erythropoiesis characterized by decreased complexity of global miRNA expression and reciprocally increased expression of individual lineage-specific miRNAs. Interestingly, against a backdrop of evident clustering and thus similarity of same-stage hCD34+ and HUDEP-2 cells, differential expression of several miRNAs highlighted readily interpretable discrepancies between both cell types. Moreover, differential expression analysis between the closely related HUDEP-2 and HUDEP-1 cells provided pointers to miRNAs, transcription factors (TFs), target genes, and pathways mechanistically linked to globin switching. In resulting TF-miRNA co-regulatory networks, TFs known to be implicated in hemoglobin switching, including the major γ-globin repressors BCL11A and ZBTB7A, were targeted by many co-regulated miRNAs, outlining intricate combinatorial miRNA regulation of globin expression in erythroid cells.

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The glucocorticoid receptor elicited proliferative response in human erythropoiesis is BCL11A-dependent

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