Abstract

During development, inflammation or tissue injury, macrophages engulf multiple apoptotic cells via efferocytosis to maintain tissue homeostasis. The mechanism by which macrophages rapidly adapt their transcription for continuous corpse uptake is not well understood. Transcriptional pause/release is a conserved mechanism, in which RNA polymerase (Pol) II initiates transcription for 20-60 nucleotides, is paused for minutes to hours and is then released to the elongation phase. We show that macrophages quickly use Pol II pause/release upon encountering corpses to trigger a rapid transcriptional response. This mechanism is essential for continuous efferocytosis but does not affect other forms of phagocytosis. Genomic data integration from precision nuclear run-on sequencing, RNA sequencing, and assay for transposase-accessible chromatin using sequencing (ATAC-seq) reveals that Pol II pause/release controls the expression of various transcription factors such as EGR3 and downstream target genes. Using lysosomal probes and a new genetic fluorescent reporter, we identify a role for pause/release in phagosome acidification during efferocytosis. Collectively, these data indicate that macrophages use Pol II pause/release as a mechanism to rapidly alter their transcriptional programs for efficient processing of the ingested apoptotic corpses and for successive efferocytosis.

Committee Chair

Kodi Ravichandran

Committee Members

Eynav Klechevsky; Kenneth Murphy; Kodi Ravichandran; Kyunghee Choi; Maxim Artyomov; Ting Wang

Degree

Doctor of Philosophy (PhD)

Author's Department

Biology & Biomedical Sciences (Molecular Cell Biology)

Author's School

Graduate School of Arts and Sciences

Document Type

Dissertation

Date of Award

10-8-2024

Language

English (en)

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