Regulation of ribosomal RNA transcription by MYC in hematopoiesis

The National Heart, Lung, and Blood Institute awarded the University of Pennsylvania $100,228 on December 1, 2026, under the Cardiovascular Diseases Research program (CFDA 93.837) to conduct research on the regulation of ribosomal RNA transcription by MYC in hematopoiesis.

The funded research dissects how MYC, a developmental transcription factor often dysregulated in disease, directly regulates ribosomal RNA (rRNA) transcription by RNA polymerase I in hematopoietic cells. The work addresses a fundamental knowledge gap: while MYC binds to ribosomal DNA, significant uncertainty remains about whether and how MYC directly regulates polymerase I activity. Disruption of rRNA transcription contributes to hematopoietic disorders including Diamond Blackfan anemia and Schwachman-Diamond syndrome. The investigator will determine the direct step of rRNA transcription regulated by MYC by assessing changes in chromatin occupancy of rRNA transcriptional machinery and changes in the quantity of active rRNA gene repeats following acute MYC degradation, and will test whether MYC restoration directly restores transcriptional activation.

The award runs through June 30, 2029, with place of performance at Philadelphia, Pennsylvania. This is a Project Grant, the standard investigator-initiated research mechanism under NHLBI's portfolio.

Abstract

Ribosomal RNA (rrna) transcription by RNA polymerase i (POL i) is a tightly regulated process in hematopoiesis and its rate varies drastically between hematopoietic cell types. Rrna transcription is a critical, rate-limiting step of ribosome biogenesis, a process by which precise regulation is critical for cell growth, proliferation, and differentiation. IT's importance in hematopoiesis is underscored by the fact that its disruption can lead to hematopoietic disorders including diamond blackfan anemia and schwachman-diamond syndrome. While the role of lineage specific transcription factors in regulating RNA polymerase II (POL II) is well understood, the factors and mechanisms governing the cell-type specific rate of rrna transcription by POL i remains largely unexplored. IT has been shown that MYC binds to ribosomal DNA (rdna), but there is significant discourse as to whether or how MYC directly regulates POL i, leading to a fundamental knowledge GAP in hematopoiesis and cell biology at large. This proposal will thoroughly dissect how MYC, a critical developmental transcription factor that is often dysregulated in disease, directly regulates rrna transcription by POL i in hematopoiesis. Acute MYC degradation in a human myeloid cell line leads to a significant and biologically relevant reduction of rrna transcription before any appreciable change in the protein level of core rrna transcriptional machinery. The exact mechanism by which MYC is mediating rrna transcriptional activation in hematopoiesis remains unknown. The first goal of this proposal is to determine the direct step of rrna transcription that is regulated by MYC. I will assess changes in chromatin occupancy of rrna transcriptional machinery and changes in the quantity of activate rdna repeats following acute MYC degradation. Further, i will test this effect to be direct by determining if MYC restoration in the presence of a POL II-inhibitor can rescue rrna transcription. The second goal is to use acute MYC degradation paired with a GFP-c-MYC mouse model to provide the first detailed quantification of how MYC protein level correlates with rrna transcription and nucleolar size (the origin site of rrna transcription) throughout hematopoiesis. Additionally, i will determine whether MYC exhibits differential occupancy at rdna in three primary hematopoietic cell types to further uncover the potential mechanisms governing the varying rrna transcription rates throughout hematopoiesis. I hypothesize that MYC directly promotes POL i occupancy on rdna leading to proportional output of rrna transcription in hematopoietic cell types. This study will reveal mycs role in the transcriptional regulation of rrna, the most abundant RNA in the cell. These findings will be broadly relevant to normal and diseased hematopoiesis and will uncover the potential factors and mechanisms by which hematopoietic cells fine-tune their rates of rrna transcription.