# Characterization of the role of ZSWIM8 and target-directed microRNA degradation in hematopoiesis

> **NIH NIH F30** · HARVARD MEDICAL SCHOOL · 2024 · $53,974

## Abstract

PROJECT SUMMARY
Thrombocytopenia (low platelet count) is a significant problem that can cause life-threatening hemorrhage.
Platelets are produced by megakaryocytes (MKs), which differentiate from hematopoietic stem cells (HSCs).
Due to a lack of understanding of the fundamental processes driving MK differentiation, therapeutic strategies
for thrombocytopenia remain limited. MicroRNAs are small noncoding RNAs that repress gene expression by
directing silencing machinery to mRNA targets. Dozens of microRNAs have been implicated in hematopoiesis,
or the production of mature blood cells from HSCs. Most microRNAs are long-lived in cells (up to several
days), but some are actively degraded in a process termed target-directed microRNA degradation (TDMD),
which is mediated by the protein ZSWIM8. TDMD rapidly depletes cells of specific microRNAs, thus relieving
repression on their target mRNAs. Homozygous knockout (KO) of Zswim8 in mice leads to 100% perinatal
lethality and increased expression >50 microRNAs (ZSWIM8-sensitive microRNAs) in at least one embryonic
tissue examined, highlighting ZSWIM8’s physiologic importance. Several of these ZSWIM8-sensitive
microRNAs have been previously implicated in hematopoiesis. Limited published data suggest a particularly
important role for microRNA decay mechanisms in MK differentiation, as numerous microRNAs are reported to
be downregulated during MK maturation. Further, preliminary results from Zswim8 KO mouse embryos showed
that out of all cell lineages assessed, the largest effect was in the MK lineage. Hematopoiesis is a stepwise
process that requires sequential shifts in the HSC’s gene expression profile as it differentiates into
progressively restricted cell types, which may necessitate active degradation of microRNAs that would
otherwise persist in the cell for several days. Therefore, the central hypothesis of this proposal is that ZSWIM8-
mediated TDMD remodels the cellular microRNA environment to promote gene expression shifts during
hematopoietic differentiation. Currently, there is no published information on the role of ZSWIM8-mediated
TDMD in hematopoiesis. Aim 1 seeks to characterize the effect of ZSWIM8-mediated TDMD on mammalian
hematopoiesis in the fetal and adult stages, as well as during reconstitution of the hematopoietic stem cell
niche after bone marrow transplant. Aim 2 focuses on the apparent role of ZSWIM8-mediated TDMD in MK
differentiation. MKs will be derived from murine primary cell cultures. Small-RNA sequencing of these cultured
MKs will identify microRNAs that are degraded by ZSWIM8-mediated TDMD. Overexpression experiments will
pinpoint the microRNAs able to explain the ZSWIM8-dependent MK differentiation phenotype. Pairing these
analyses with bulk RNA sequencing will implicate downstream gene regulatory networks impacted by ZSWIM8.
Altogether, this work will elucidate the role of ZSWIM8-mediated TDMD on cell fate specialization and uncover
novel roles for microRNA regulation in m...

## Key facts

- **NIH application ID:** 10996325
- **Project number:** 1F30HL175923-01
- **Recipient organization:** HARVARD MEDICAL SCHOOL
- **Principal Investigator:** Lara Elcavage
- **Activity code:** F30 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $53,974
- **Award type:** 1
- **Project period:** 2024-09-01 → 2027-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10996325

## Citation

> US National Institutes of Health, RePORTER application 10996325, Characterization of the role of ZSWIM8 and target-directed microRNA degradation in hematopoiesis (1F30HL175923-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10996325. Licensed CC0.

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