Abstract
Maintenance of quiescence and DNA replication dynamics are 2 paradoxical requirements
for the distinct states of dormant and active hematopoietic stem cells (HSCs), which are
required to preserve the stem cell reservoir and replenish the blood cell system in
response to hematopoietic stress, respectively. Here, we show that key self-renewal
factors, β-catenin or Hoxa9, largely dispensable for HSC integrity, in fact, have dual
functions in maintaining quiescence and enabling efficient DNA replication fork dynamics
to preserve the functionality of hematopoietic stem and progenitor cells (HSPCs).
Although β-catenin or Hoxa9 single knockout (KO) exhibited mostly normal hematopoiesis,
their coinactivation led to severe hematopoietic defects stemmed from aberrant cell
cycle, DNA replication, and damage in HSPCs. Mechanistically, β-catenin and Hoxa9
function in a compensatory manner to sustain key transcriptional programs that converge
on the pivotal downstream target and epigenetic modifying enzyme, Prmt1, which protects
the quiescent state and ensures an adequate supply of DNA replication and repair
factors to maintain robust replication fork dynamics. Inactivation of Prmt1 phenocopied both cellular and molecular
phenotypes of β-catenin/Hoxa9 combined KO, which at the same time could also be partially rescued by Prmt1
expression. The discovery of the highly resilient β-catenin/Hoxa9/Prmt1 axis in protecting both quiescence and DNA
replication dynamics essential for HSCs at different key states provides not only novel mechanistic insights into their
intricate regulation but also a potential tractable target for therapeutic intervention.
for the distinct states of dormant and active hematopoietic stem cells (HSCs), which are
required to preserve the stem cell reservoir and replenish the blood cell system in
response to hematopoietic stress, respectively. Here, we show that key self-renewal
factors, β-catenin or Hoxa9, largely dispensable for HSC integrity, in fact, have dual
functions in maintaining quiescence and enabling efficient DNA replication fork dynamics
to preserve the functionality of hematopoietic stem and progenitor cells (HSPCs).
Although β-catenin or Hoxa9 single knockout (KO) exhibited mostly normal hematopoiesis,
their coinactivation led to severe hematopoietic defects stemmed from aberrant cell
cycle, DNA replication, and damage in HSPCs. Mechanistically, β-catenin and Hoxa9
function in a compensatory manner to sustain key transcriptional programs that converge
on the pivotal downstream target and epigenetic modifying enzyme, Prmt1, which protects
the quiescent state and ensures an adequate supply of DNA replication and repair
factors to maintain robust replication fork dynamics. Inactivation of Prmt1 phenocopied both cellular and molecular
phenotypes of β-catenin/Hoxa9 combined KO, which at the same time could also be partially rescued by Prmt1
expression. The discovery of the highly resilient β-catenin/Hoxa9/Prmt1 axis in protecting both quiescence and DNA
replication dynamics essential for HSCs at different key states provides not only novel mechanistic insights into their
intricate regulation but also a potential tractable target for therapeutic intervention.
| Original language | English |
|---|---|
| Pages (from-to) | 1586-1598 |
| Number of pages | 13 |
| Journal | Blood |
| Volume | 143 |
| Issue number | 16 |
| DOIs | |
| Publication status | Published - 18 Apr 2024 |