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Hematopoiesis and Erythropoiesis

A major focus of our laboratory is understanding the regulation of gene expression in normal and perturbed hematopoiesis, particularly erythropoiesis. We have studied the influence of specific transcription factors and epigenetic factors on chromatin architecture and DNA methylation on entire programs of gene expression in hematopoietic development. We have applied genomic strategies, including mRNA and microRNA expression profiling, single cell sequencing, RNA seq, ChIP-chip and ChIP-seq technology, ATAC sequencing, meDIP and other methylation methodologies, as well as novel phosphoproteomic and quantitative proteomic techniques, to our understanding of hematopoiesis. We have studied gene regulation in human iPS cells, hematopoietic stem and progenitor cells, T follicular helper, T effector, naïve T lymphocytes, germinal center B lymphocytes, and erythroid cells at varying stages of development and differentiation. We utilize erythroid cells and specific membrane protein gene loci as models of regulation of complex genetic loci, a model which has many benefits. The genes are large and are represented by many cell, tissue, and developmental stage-specific isoforms. We utilize a number of cellular models including hematopoietic stem cells, ES cells, iPS cells, and transformed cell lines in genomic and relevant functional studies.

Our studies demonstrated that the transcription factor KLF1/EKLF, an erythroid-specific, C2H2-type zinc-finger transcription factor, known to regulate beta-globin gene expression, also regulates numerous nonglobin genes encoding proteins with a variety of functions including cell cycle regulation, erythrocyte membrane structural proteins, and globin chaperones. Our studies have demonstrated that barrier insulators, elements critical for controlling tissue-specific gene expression, regulate erythroid-cell specific transcripts and that when mutated, lead to a disease phenotype. We have identified various cell type enhancers, including erythroid cell enhancers, T follicular helper cell enhancers and others, and have linked them to loci associated with relevant cell type-specific phenotypic traits and diseases. We have shown major changes in gene expression throughout human erythroid development and differentiation.

Chromatin accessibility at the beta-globin locus during erythroid development and differentiation in human umbilical-derived erythroid cells.

A heatmap of gene expression during erythroid development and differentiation in human umbilical cord-derived cells.