# Mechanisms and relevance of miRNA decay during hematopoietic development

> **NIH NIH R01** · WASHINGTON UNIVERSITY · 2024 · $657,368

## Abstract

PROJECT SUMMARY/ABSTRACT
MicroRNAs (miRNAs) are essential regulators of the human transcriptome and play a central role in
tissue development. As the hematopoietic system is composed of a multitude of mature cell types constantly
produced from stem and progenitor cells, it is not surprising that correct miRNA biogenesis, function, and decay
are essential for hematopoietic differentiation. We have recently identified U6 Biogenesis 1 (USB1) as being a
novel 3·_ end miRNA deadenylase that regulates degradation of different miRNAs. As mutations in USB1 cause
the bone marrow failure syndrome poikiloderma with neutropenia (PN), it becomes clear that the correct 3· - end
processing of miRNAs by USB1 is critical for hematopoiesis. Due to a lack of adequate models and intrinsic
difficulties in studying mi RNA processing, the pathways that control miRNA degradation remain largely unknown.
A better understanding of the posttranscriptional regulation of miRNA processing, and how it relates to activation
of different miRNA degradation pathways is essential to decipher the role of these non-coding RNAs during
hematopoiesis.
The focus of this proposal is to use the targeted hematopoietic differentiation of human pluripotent stem
cells to decipher molecular pathways controlling posttranscriptional regulation and degradation routes of
miRNAs. We have generated a large panel of human pluripotent stem cell lines harboring pathogenic mutations
in USB1 and other miRNA 3'-end deadenylases, as well as mutations in different components of the exosome
RNA decay complex. From these, we derive hematopoietic cells in vitro, following established protocols that
recapitulate the in vivo formation of these cell types.
Two specific aims are proposed that utilize this platform to identify novel regulators of miRNA processing
and decay, and to determine their function in the hematopoietic system. Aim 1 will determine the mechanisms
regulating target specificity and overlap of different deadenylases necessary for development, during several
stages of hematopoiesis. We will complement these assays by determining which miRNA decay routes are
activated in these cellular populations, focusing on exosome activation and target-directed miRNA degradation
(TDMD). We will determine to which extent TDMD is modulated by incorrect miRNA 3'- end adenylation and
deadenylation in WT and USB1 mutants. Aim 2 will investigate the specific mechanisms leading to impaired
neutrophil development in USB 1 mutant cells, as PN causes severe non-cyclic neutropenia. We have identified
potential targets of USB 1 that modulate neutrophil yield and will test their functional role in different processes,
such as cellular replication and apoptosis, that could lead to a failure of myeloid progenitors to efficiently generate
neutrophils.
These studies will decipher novel effectors of miRNA degradation in the hematopoietic system, a tissue
where miRNA-regulated gene expression plays a central role. Our unique molec...

## Key facts

- **NIH application ID:** 10941648
- **Project number:** 1R01HL174789-01
- **Recipient organization:** WASHINGTON UNIVERSITY
- **Principal Investigator:** Luis Francisco Zirnberger Batista
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $657,368
- **Award type:** 1
- **Project period:** 2024-08-01 → 2028-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10941648

## Citation

> US National Institutes of Health, RePORTER application 10941648, Mechanisms and relevance of miRNA decay during hematopoietic development (1R01HL174789-01). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10941648. Licensed CC0.

---

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