# Elucidating the Role of Integrator Complex in Erythropoiesis

> **NIH NIH R01** · UNIVERSITY OF ROCHESTER · 2024 · $385,000

## Abstract

PROJECT SUMMARY
 Erythropoiesis is a finely orchestrated process that involves generating a ~2.5 million red blood
cells per second to maintain homeostasis and prevent anemia. During terminal maturation, erythroid
precursors upregulate erythroid-specific genes while silencing non-erythroid genes in the setting of a cell
that is rapidly dividing and a nucleus that is condensing in preparation for enucleation. Our group has
shown that regulation of RNAPII activity is an essential determinant of erythroid cell function. During
terminal erythroid maturation, RNA polymerase II (RNAPII) levels decline dramatically, becoming a
scarce resource allocated to erythroid genes, such as alpha and beta globin. The mechanism(s) by which
RNAPII is removed from genes unnecessary to erythroid differentiation and shunted to produce mRNA
essential for red blood cell function is unknown. The Integrator Complex (INT) is a multi-subunit
machinery that associates with RNA polymerase II (RNAPII) and functions as a critical transcription
regulator. It is a broad negative regulator of promoter-proximally paused RNAPII. Integrator subunit 11
(INTS11) houses the RNA endonuclease domain vital for Integrator to cleave nascent transcripts at all
RNAPII loci, which is an important activity for transcriptional repression and the processing of eRNA.
 Although INT is highly expressed in maturing erythroid cells, little is known about its function in
erythropoiesis. Further, the role of promoter-proximal transcriptional termination in regulating erythroid
gene expression has been almost completely unexplored. Our preliminary data reveal that disruption of
INT impairs the proliferation and maturation of primary human erythroid cells. Our CUT&RUN analyses
in primary erythroid cells uncover that INT is present at genes containing stably paused RNAPII that is
subsequently lost before enucleation. Finally, we find that INT binds to erythroid enhancers, including the
beta-globin LCR, in a manner correlating with increased transcription. Altogether, these data support a
hypothesis where INT enforces RNAPII pausing and termination at non-erythroid genes to maintain
RNAPII availability while enhancing the transcription of erythroid genes through eRNA processing. To
test this hypothesis, we propose two specific aims: Specific Aim1. Determine the function of the Integrator
Complex during terminal erythroid maturation. Specific Aim 2. Delineate mechanisms by which Integrator
regulates erythroid gene expression.

## Key facts

- **NIH application ID:** 10901169
- **Project number:** 1R01HL173979-01
- **Recipient organization:** UNIVERSITY OF ROCHESTER
- **Principal Investigator:** LAURIE A. STEINER
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $385,000
- **Award type:** 1
- **Project period:** 2024-04-01 → 2028-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10901169

## Citation

> US National Institutes of Health, RePORTER application 10901169, Elucidating the Role of Integrator Complex in Erythropoiesis (1R01HL173979-01). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10901169. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*