microRNAs (miRNA) play an important role in immune system development and function, often participating in regulatory networks with the transcription factors (TFs) that drive their expression. However, many of these relationships remain obscured because regulatory elements controlling miRNA expression in different immune cells are largely uncharacterized. Moreover, the miRNAs participating in regulatory functions are not known in many immune cells that lack or have undergone limited miRNA abundance profiling. To address this, we analyzed miRNA expression and open chromatin regions (OCR) from >60 immune cell populations in a joint manner. We profiled the miRNA compartment of 63 populations of immune cells, including myeloid and lymphoid cell types, as well endothelial cells and fibroblasts, isolated in steady-state or following perturbation. Comparative benchmarks were used, including standard curves and miRNA sensors, to establish an expression threshold correlating with miRNA activity. This indicated a low complexity in the miRNA regulatory fraction of each cell type; comprised of <75 miRNAs. Despite the low complexity, we still found unique miRNA signatures across the immune system, even between closely related populations, such as different tissue-resident macrophages.Connecting chromatin accessibility to miRNA expression enabled us to establish maps of miRNA promoter and enhancer usage across the immune system. Unique miRNA signatures within different populations were associated with local chromatin accessibility changes, revealing putative regulatory elements for differentially expressed miRNAs. These maps suggest many miRNAs utilize multiple promoters to increase abundance, and also identified dominant and divergent miRNA regulatory elements between lineages and during immune cell development, as well as between closely clustered miRNAs. We also found significant variability in target abundance for each cellular miRNA, sometimes skewed by highly expressed genes in a particular population. This thesis provides insight into the miRNA regulatory network of the immune system and is a resource for further discovery.
|Advisor:||Brown, Brian D.|
|Commitee:||Sealfon, Stuart, Faith, Jeremiah, Ma'ayan, Avi, Houten, Sander, Hernando, Eva|
|School:||Icahn School of Medicine at Mount Sinai|
|Department:||Genetics and Genomic Sciences|
|School Location:||United States -- New York|
|Source:||DAI-B 82/5(E), Dissertation Abstracts International|
|Subjects:||Genetics, Immunology, Cellular biology, Developmental biology|
|Keywords:||microRNA, Immune system|
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