ERα promotes murine hematopoietic regeneration through the Ire1α-mediated unfolded protein response
- Baylor College of Medicine, United States
- University of Michigan, United States
- Kanazawa Medical University, Japan
Abstract
Activation of the unfolded protein response (UPR) sustains protein homeostasis (proteostasis) and plays a fundamental role in tissue maintenance and longevity of organisms. Long-range control of UPR activation has been demonstrated in invertebrates, but such mechanisms in mammals remain elusive. Here, we show that the female sex hormone estrogen regulates the UPR in hematopoietic stem cells (HSCs). Estrogen treatment increases the capacity of HSCs to regenerate the hematopoietic system upon transplantation and accelerates regeneration after irradiation. We found that estrogen signals through estrogen receptor α (ERα) expressed in hematopoietic cells to activate the protective Ire1α-Xbp1 branch of the UPR. Further, ERα-mediated activation of the Ire1α-Xbp1 pathway confers HSCs with resistance against proteotoxic stress and promotes regeneration. Our findings reveal a systemic mechanism through which HSC function is augmented for hematopoietic regeneration.
Data availability
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RNA-Seq of hematopoietic stem cells from vehicle and estrogen-treated micePublicly available at the NCBI Gene Expression Omnibus (accession no: GSE99120).
Article and author information
Author details
Funding
National Cancer Institute (CA193235)
- Daisuke Nakada
National Heart, Lung, and Blood Institute (HL132392)
- Qing Li
National Institute of Diabetes and Digestive and Kidney Diseases (DK107413)
- Daisuke Nakada
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Ethics
Animal experimentation: Mice were housed in AAALAC-accredited, specific-pathogen-free animal care facilities at Baylor College of Medicine (BCM), or University of Michigan (UM) with 12hr light-dark cycle and received standard chow ad libitum. All procedures were approved by the BCM or UM Institutional Animal Care and Use Committees (protocol #AN-5858).
Copyright
© 2018, Chapple et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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ERα promotes murine hematopoietic regeneration through the Ire1α-mediated unfolded protein response
eLife 7:e31159.
https://doi.org/10.7554/eLife.31159
Further reading
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- Neuroscience
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Sensory dorsal root ganglion (DRG) neurons have a unique pseudo-unipolar morphology in which a stem axon bifurcates into a peripheral and a central axon, with different regenerative abilities. Whereas peripheral DRG axons regenerate, central axons are unable to regrow. Central axon regeneration can however be elicited by a prior conditioning lesion to the peripheral axon. How DRG axon asymmetry is established remains unknown. Here we developed a rodent in vitro system replicating DRG pseudo-unipolarization and asymmetric axon regeneration. Using this model, we observed that from early development, central DRG axons have a higher density of growing microtubules. This asymmetry was also present in vivo and was abolished by a conditioning lesion that decreased microtubule polymerization of central DRG axons. An axon-specific microtubule-associated protein (MAP) signature, including the severases spastin and katanin and the microtubule regulators CRMP5 and tau, was found and shown to adapt upon conditioning lesion. Supporting its significance, interfering with the DRG MAP signature either in vitro or in vivo readily abolished central-peripheral asymmetries in microtubule dynamics and regenerative ability. In summary, our data unveil that axon-specific microtubule regulation drives asymmetric regeneration of sensory neuron axons.
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- Developmental Biology
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Chromocenters are established after the 2-cell (2C) stage during mouse embryonic development, but the factors that mediate chromocenter formation remain largely unknown. To identify regulators of 2C heterochromatin establishment in mice, we generated an inducible system to convert embryonic stem cells (ESCs) to 2C-like cells. This conversion is marked by a global reorganization and dispersion of H3K9me3-heterochromatin foci, which are then reversibly formed upon re-entry into pluripotency. By profiling the chromatin-bound proteome (chromatome) through genome capture of ESCs transitioning to 2C-like cells, we uncover chromatin regulators involved in de novo heterochromatin formation. We identified TOPBP1 and investigated its binding partner SMARCAD1. SMARCAD1 and TOPBP1 associate with H3K9me3-heterochromatin in ESCs. Interestingly, the nuclear localization of SMARCAD1 is lost in 2C-like cells. SMARCAD1 or TOPBP1 depletion in mouse embryos leads to developmental arrest, reduction of H3K9me3, and remodeling of heterochromatin foci. Collectively, our findings contribute to comprehending the maintenance of chromocenters during early development.
