Epigenetic programming defines haematopoietic stem cell fate restriction
Haematopoietic stem cells (HSCs) are multipotent, but individual HSCs can show restricted lineage output in vivo. Currently, the molecular mechanisms and physiological role of HSC fate restriction remain unknown. Here we show that lymphoid fate is epigenetically but not transcriptionally primed in H...
| Main Authors: | , , , , , , , , , |
|---|---|
| Format: | Journal article |
| Language: | English |
| Published: |
Springer Nature
2023
|
| _version_ | 1826310650058506240 |
|---|---|
| author | Meng, Y de Teixeira Carrelha, J Drissen, R Ren, X Zhang, B Gambardella, A Valletta, S Thongjuea, S Jacobsen, SE Nerlov, C |
| author_facet | Meng, Y de Teixeira Carrelha, J Drissen, R Ren, X Zhang, B Gambardella, A Valletta, S Thongjuea, S Jacobsen, SE Nerlov, C |
| author_sort | Meng, Y |
| collection | OXFORD |
| description | Haematopoietic stem cells (HSCs) are multipotent, but individual HSCs
can show restricted lineage output in vivo. Currently, the molecular
mechanisms and physiological role of HSC fate restriction remain unknown.
Here we show that lymphoid fate is epigenetically but not transcriptionally
primed in HSCs. In multi-lineage HSCs that produce lymphocytes,
lymphoid-specific upstream regulatory elements (LymUREs) but not
promoters are preferentially accessible compared with platelet-biased HSCs
that do not produce lymphoid cell types, providing transcriptionally silent
lymphoid lineage priming. Runx3 is preferentially expressed in multi-lineage
HSCs, and reinstating Runx3 expression increases LymURE accessibility
and lymphoid-primed multipotent progenitor 4 (MPP4) output in old,
platelet-biased HSCs. In contrast, platelet-biased HSCs show elevated levels
of epigenetic platelet-lineage priming and give rise to MPP2 progenitors
with molecular platelet bias. These MPP2 progenitors generate platelets
with faster kinetics and through a more direct cellular pathway compared
with MPP2s derived from multi-lineage HSCs. Epigenetic programming
therefore predicts both fate restriction and differentiation kinetics in HSCs. |
| first_indexed | 2024-03-07T07:56:34Z |
| format | Journal article |
| id | oxford-uuid:c71a095f-9046-4372-a9aa-7f30de7eeadc |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-07T07:56:34Z |
| publishDate | 2023 |
| publisher | Springer Nature |
| record_format | dspace |
| spelling | oxford-uuid:c71a095f-9046-4372-a9aa-7f30de7eeadc2023-08-17T08:57:53ZEpigenetic programming defines haematopoietic stem cell fate restrictionJournal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:c71a095f-9046-4372-a9aa-7f30de7eeadcEnglishSymplectic ElementsSpringer Nature2023Meng, Yde Teixeira Carrelha, JDrissen, RRen, XZhang, BGambardella, AValletta, SThongjuea, SJacobsen, SENerlov, CHaematopoietic stem cells (HSCs) are multipotent, but individual HSCs can show restricted lineage output in vivo. Currently, the molecular mechanisms and physiological role of HSC fate restriction remain unknown. Here we show that lymphoid fate is epigenetically but not transcriptionally primed in HSCs. In multi-lineage HSCs that produce lymphocytes, lymphoid-specific upstream regulatory elements (LymUREs) but not promoters are preferentially accessible compared with platelet-biased HSCs that do not produce lymphoid cell types, providing transcriptionally silent lymphoid lineage priming. Runx3 is preferentially expressed in multi-lineage HSCs, and reinstating Runx3 expression increases LymURE accessibility and lymphoid-primed multipotent progenitor 4 (MPP4) output in old, platelet-biased HSCs. In contrast, platelet-biased HSCs show elevated levels of epigenetic platelet-lineage priming and give rise to MPP2 progenitors with molecular platelet bias. These MPP2 progenitors generate platelets with faster kinetics and through a more direct cellular pathway compared with MPP2s derived from multi-lineage HSCs. Epigenetic programming therefore predicts both fate restriction and differentiation kinetics in HSCs. |
| spellingShingle | Meng, Y de Teixeira Carrelha, J Drissen, R Ren, X Zhang, B Gambardella, A Valletta, S Thongjuea, S Jacobsen, SE Nerlov, C Epigenetic programming defines haematopoietic stem cell fate restriction |
| title | Epigenetic programming defines haematopoietic stem cell fate restriction |
| title_full | Epigenetic programming defines haematopoietic stem cell fate restriction |
| title_fullStr | Epigenetic programming defines haematopoietic stem cell fate restriction |
| title_full_unstemmed | Epigenetic programming defines haematopoietic stem cell fate restriction |
| title_short | Epigenetic programming defines haematopoietic stem cell fate restriction |
| title_sort | epigenetic programming defines haematopoietic stem cell fate restriction |
| work_keys_str_mv | AT mengy epigeneticprogrammingdefineshaematopoieticstemcellfaterestriction AT deteixeiracarrelhaj epigeneticprogrammingdefineshaematopoieticstemcellfaterestriction AT drissenr epigeneticprogrammingdefineshaematopoieticstemcellfaterestriction AT renx epigeneticprogrammingdefineshaematopoieticstemcellfaterestriction AT zhangb epigeneticprogrammingdefineshaematopoieticstemcellfaterestriction AT gambardellaa epigeneticprogrammingdefineshaematopoieticstemcellfaterestriction AT vallettas epigeneticprogrammingdefineshaematopoieticstemcellfaterestriction AT thongjueas epigeneticprogrammingdefineshaematopoieticstemcellfaterestriction AT jacobsense epigeneticprogrammingdefineshaematopoieticstemcellfaterestriction AT nerlovc epigeneticprogrammingdefineshaematopoieticstemcellfaterestriction |