# Transcript decay regulates hematopoietic aging

> **NIH NIH R01** · BAYLOR COLLEGE OF MEDICINE · 2020 · $356,625

## Abstract

ABSTRACT
The overall goal of our research is to investigate molecular mechanisms of aging in hematopoietic stem cells
(HSCs). Hematopoiesis requires high levels of cellular regeneration, including the production of billions of
platelets, erythrocytes and immune cells on a daily basis. HSC function declines with age, a process that has
been implicated in the rise of infections, cancers, rheumatoid, and cardiovascular diseases.
 Molecular changes during aging, especially those involving genetic and epigenetic mechanisms are being
investigated by several groups. These pathways mostly impact de novo transcription of genes. In contrast, little
is known about changes affecting the post-transcriptional fate of mRNA during aging. To better understand the
role of mRNA decay, we investigated the poly-A binding protein C1 (PABPC1), a key regulator of transcript
turnover in the cytosol. We found a novel interaction between the prolyl-isomerase cyclophilin A and PABPC1.
Our data suggest that cyclophilin A alters the structure of PABPC1 to facilitate mRNA elimination. Depletion of
cyclophilin A stabilizes transcripts by slowing mRNA decay.
 To study the impact of mRNA turnover on hematopoiesis, we performed a suite of functional assays using
cyclophilin A-deficient mice. HSCs lacking the prolyl-isomerase display the hallmarks of aging, including
increased cell division, myeloid skewing, and stem cell exhaustion. Importantly, gene expression profiling
revealed that cyclophilin A deficiency and native aging share similar changes to the transcriptome. In cells lacking
cyclophilin A, these are caused by reduced mRNA decay. Moreover, we provide evidence that mRNA turnover
is also slowing down in physiologically aged hematopoietic cells.
 Based on this evidence, we hypothesize that reduced mRNA decay rates in aged HSCs alter the
transcriptome and that these changes promote aging in the hematopoietic compartment. We will formally
test this hypothesis using molecular, cellular, and newly developed in vivo models. Specifically, we will (A)
quantify mRNA levels and mRNA turnover in HSCs during aging, (B) investigate molecular causes for altered
mRNA decay in old cells, and (C) determine whether delayed mRNA clearance contributes to oligoclonality with
age. Successful implementation of these aims will further our understanding of the post-transcriptional changes
that shape hematopoietic stem cell aging. Focusing on the dynamics of mRNA turnover will add a conceptually
novel dimension to existing work on gene transcription in the hematopoietic system.

## Key facts

- **NIH application ID:** 9976516
- **Project number:** 5R01DK115454-04
- **Recipient organization:** BAYLOR COLLEGE OF MEDICINE
- **Principal Investigator:** Andre Catic
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $356,625
- **Award type:** 5
- **Project period:** 2017-09-15 → 2022-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9976516

## Citation

> US National Institutes of Health, RePORTER application 9976516, Transcript decay regulates hematopoietic aging (5R01DK115454-04). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9976516. Licensed CC0.

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