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Department of Animal Sciences
The Robert H. Smith Faculty
of Agricultural, Food & Environment

The Hebrew University of Jerusalem.

Herzl 229, Rehovot 7610001, Israel
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Ribarski-Chorev, I. ; Schudy, G. ; Strauss, C. ; Schlesinger, S. Short heat shock has a long-term effect on mesenchymal stem cells’ transcriptome. bioRxiv 2022. Publisher's VersionAbstract
Background: Mesenchymal stem cells (MSCs) are multipotent stromal, non-hematopoietic cells with self-renewal and differentiation properties and are therefore a preferred source for cellular therapies. However, a better understanding of culture techniques is required to harness their full potential. Here we aim to compare the effects of short and long heat shock (HS) on the transcriptomic landscape of MSCs. Methods: MSCs were extracted from the umbilical cord of a bovine fetus, cultured, and validated as MSCs. Early passage cells were exposed to 40.5°C for six hours or three days. RNA sequencing and bioinformatics analysis were performed to systematically examine the transcriptional changes following each treatment and to identify specific biological features and processes. Results: The data indicates that while long heat stress influences many cell processes, such as immune response, cell cycle, and differentiation, the short HS mostly upregulates the cellular stress response. Once normothermia is resumed the long-term effects of the short HS can be revealed: although most genes revert to their original expression levels, a subgroup of epigenetically marked genes termed bivalent genes, maintains high expression levels. These genes are known to support cell lineage specification and are carefully regulated by a group of chromatin modifiers. One family of those chromatin modifiers, called MLL genes, is highly over-represented in the transiently upregulated cluster after six hours of HS. Therefore, our data provide a mechanistic explanation for the long-term phenotype of short HS on development-related genes and could be used to predict the long-term effect of HS on cell identity. Conclusions: Understanding the influence of culture conditions on morphology, phenotype, proliferative capacity, and fate decision of MSCs is needed to optimize culture conditions suitable for clinical or commercial use. Here, we suggest that simple and short stress can alter the cell’s proliferation and differentiation capacities and, therefore, following future optimizations, be used to shift the cells toward a more desirable functionality.Competing Interest StatementThe authors have declared no competing interest.
Margalit, L. ; Strauss, C. ; Tal, A. ; Schlesinger, S. Trim24 and Trim33 Play a Role in Epigenetic Silencing of Retroviruses in Embryonic Stem Cells. VIRUSES-BASEL 2020, 12.Abstract
Embryonic stem cells (ESC) have the ability to epigenetically silence endogenous and exogenous retroviral sequences. Trim28 plays an important role in establishing this silencing, but less is known about the role other Trim proteins play. The Tif1 family is a sub-group of the Trim family, which possess histone binding ability in addition to the distinctive RING domain. Here, we have examined the interaction between three Tif1 family members, namely Trim24, Trim28 and Trim33, and their function in retroviral silencing. We identify a complex formed in ESC, comprised of these three proteins. We further show that when Trim33 is depleted, the complex collapses and silencing efficiency of both endogenous and exogenous sequences is reduced. Similar transcriptional activation takes place when Trim24 is depleted. Analysis of the H3K9me3 chromatin modification showed a decrease in this repressive mark, following both Trim24 and Trim33 depletion. As Trim28 is an identified binding partner of the H3K9 methyltransferase ESET, this further supports the involvement of Trim28 in the complex. The results presented here suggest that a complex of Tif1 family members, each of which possesses different specificity and efficiency, contributes to the silencing of retroviral sequences in ESC.
Shimoni, C. ; Goldstein, M. ; Ribarski-Chorev, I. ; Schauten, I. ; Nir, D. ; Strauss, C. ; Schlesinger, S. Heat Shock Alters Mesenchymal Stem Cell Identity and Induces Premature Senescence. FRONTIERS IN CELL AND DEVELOPMENTAL BIOLOGY 2020, 8.Abstract
Heat stress can have a serious impact on the health of both humans and animals. A major question is how heat stress affects normal development and differentiation at both the cellular and the organism levels. Here we use anin vitroexperimental system to address how heat shock treatment influences the properties of bovine mesenchymal stem cells (MSCs)-multipotent progenitor cells-which are found in most tissues. Because cattle are sensitive to harsh external temperatures, studying the effects of heat shock on MSCs provides a unique platform to address cellular stress in a physiologically relevant model organism. Following isolation and characterization of MSCs from the cow's umbilical cord, heat shock was induced either as a pulse (1 h) or continuously (3 days), and consequent effects on MSCs were characterized. Heat shock induced extensive phenotypic changes in MSCs and dramatically curtailed their capacity to proliferate and differentiate. These changes were associated with a partial arrest in the G1/S or G2/M checkpoints. Furthermore, MSCs lost their ability to resolve the inflammatory response of RAW macrophages in coculture. A possible explanation for this loss of function is the accumulation of reactive oxygen species and malfunction of the mitochondria in the treated cells. Heat shock treatments resulted in stress-induced premature senescence, affecting the MSCs' ability to proliferate properly for many cell passages to follow. Exposure to elevated external temperatures leads to mitochondrial damage and oxidative stress, which in turn conveys critical changes in the proliferation, differentiation, and immunomodulatory phenotype of heat-stressed MSCs. A better understanding of the effect of heat shock on humans and animals may result in important health and economic benefits.
Schlesinger, S. ; Meshorer, E. Open Chromatin, Epigenetic Plasticity, and Nuclear Organization in Pluripotency. Developmental Cell 2019, 48, 135-150. Publisher's VersionAbstract
Pluripotent embryonic stem cells are considered to have open and accessible chromatin relative to differentiated cells. Schlesinger and Meshorer review chromatin and epigenetic features in 2i- versus serum-grown conditions to come to a clearer picture of the genuine characteristics of pluripotency as opposed to artifacts of culture condition. © 2019 Elsevier Inc. Pluripotent embryonic stem cells (ESCs) are considered to have open and accessible chromatin relative to differentiated cells. However, as many studies supporting these conclusions relied on ESCs grown in serum, it has been suggested that some of these features are the result of culture conditions, particularly as more recent work using GSK3/MEK inhibitors (“2i”) to mimic “ground-state” conditions of the pre-implantation blastocyst observed some altered epigenetic features. Here, we systematically review chromatin and epigenetic features in 2i- and serum-grown conditions to come to a clearer picture of what are genuine characteristics of pluripotency and what open chromatin features predict pluripotency. © 2019 Elsevier Inc.
Schlesinger, S. ; Kaffe, B. ; Melcer, S. ; Aguilera, J. D. ; Sivaraman, D. M. ; Kaplan, T. ; Meshorer, E. A hyperdynamic H3.3 nucleosome marks promoter regions in pluripotent embryonic stem cells. Nucleic Acids Research 2017, 45, 12181-12194. Publisher's VersionAbstract
Histone variants and their chaperones are key regulators of eukaryotic transcription, and are critical for normal development. The histone variant H3.3 has been shown to play important roles in pluripotency and differentiation, and although its genome-wide patterns have been investigated, little is known about the role of its dynamic turnover in transcriptional regulation. To elucidate the role of H3.3 dynamics in embryonic stem cell (ESC) biology, we generated mouse ESC lines carrying a single copy of a doxycycline (Dox)-inducible HA-tagged version of H3.3 and monitored the rate of H3.3 incorporation by ChIP-seq at varying time points following Dox induction, before and after RA-induced differentiation. Comparing H3.3 turnover profiles in ESCs and RA-treated cells, we identified a hyperdynamic H3.3-containing nucleosome at the −1 position in promoters of genes expressed in ESCs. This dynamic nucleosome is restricted and shifted downstream into the +1 position following differentiation. We suggest that histone turnover dynamics provides an additional mechanism involved in expression regulation, and that a hyperdynamic −1 nucleosome marks promoters in ESCs. Our data provide evidence for regional regulation of H3.3 turnover in ESC promoters, and calls for testing, in high resolution, the dynamic behavior of additional histone variants and other structural chromatin proteins.