Deletion of Mouse Setd4 Promotes the Recovery of Hematopoietic Failure

Copyright © 2020 The Author(s). Published by Elsevier Inc. All rights reserved..

PURPOSE: Acquired hematopoietic failure is commonly caused by therapeutic and accidental exposure of the bone marrow (BM) to toxic agents. Efficient recovery from BM failure is dictated not only by the intrinsic sensitivity and proliferation capacity of the hematopoietic stem and progenitor cells but also by the BM environment niche. Identification of genetic factors that improve recovery from hematopoietic failure is essential. Vertebrate SETD4 is a poorly characterized and putatively nonhistone methyltransferase. This study aims to identify the roles of SETD4 in BM recovery.

METHODS AND MATERIALS: An inducible SETD4 knockout mouse model (Setd4flox/flox;Rosa26-CreERT2+) was used. Adult sex-matched littermates were treated with tamoxifen to induce Setd4 deletion or oil as the control. Tamoxifen-treated Setd4wt/wt;Rosa26-CreERT2+ mice were included as another control. Those mice were irradiated to induce hematopoietic syndrome and analyzed to identify the roles and mechanisms of Setd4 in of BM recovery.

RESULTS: Loss of Setd4 in adult mice improved the survival of whole-body irradiation-induced BM failure. This was associated with improved recoveries of long-term and short-term hematopoietic stem cells (HSCs) and early progenitor cells. BM transplantation analyses surprisingly showed that the improved recovery was not due to radiation resistance of the Setd4-deficient HSCs but that Setd4-deficient HSCs were actually more sensitive to radiation. However, the Setd4-deficient mice were better recipients for allogeneic HSC transplantation. Furthermore, there was enhanced splenic erythropoiesis in Setd4-deficient mice.

CONCLUSION: These findings not only revealed a previously unrecognized role of Setd4 as a unique modulator of hematopoiesis but also underscored the critical role of the BM niche in recovery from hematopoietic failure. Our study also implicated Setd4 as a potential target for therapeutic inhibition to improve the conditioning of the BM niche before allogeneic transplantation.

Medienart:

E-Artikel

Erscheinungsjahr:

2020

Erschienen:

2020

Enthalten in:

Zur Gesamtaufnahme - volume:107

Enthalten in:

International journal of radiation oncology, biology, physics - 107(2020), 4 vom: 15. Juli, Seite 779-792

Sprache:

Englisch

Beteiligte Personen:

Feng, Xing [VerfasserIn]
Lu, Huimei [VerfasserIn]
Yue, Jingyin [VerfasserIn]
Shettigar, Megha [VerfasserIn]
Liu, Jingmei [VerfasserIn]
Denzin, Lisa K [VerfasserIn]
Shen, Zhiyuan [VerfasserIn]

Links:

Volltext

Themen:

EC 2.1.1.-
Journal Article
Methyltransferases
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Setd4 protein, mouse

Anmerkungen:

Date Completed 15.02.2021

Date Revised 16.07.2021

published: Print-Electronic

Citation Status MEDLINE

doi:

10.1016/j.ijrobp.2020.03.026

funding:

Förderinstitution / Projekttitel:

PPN (Katalog-ID):

NLM308448499