Publications by authors named "Soji Sebastian"

7 Publications

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Low-dose radiobiology program at Canadian nuclear laboratories: past, present, and future.

Int J Radiat Biol 2019 10 31;95(10):1361-1371. Epub 2019 Jan 31.

Radiobiology and Health, Canadian Nuclear Laboratories , Chalk River , Canada.

Health risks associated with the exposure of humans to low-dose ionizing radiation are currently estimated using the Linear-No-Threshold model. Over the last few decades, however, this model has been widely criticized for inconsistency with a large body of experimental evidence. Substantial efforts have been made to delineate biological mechanisms and health-related outcomes of low-dose radiation. These include a large DOE-funded Low Dose program operated in the 2000s, as well as the EU funded programs, previously NOTE and DOREMI and currently MELODI. Although not as widely known, the Atomic Energy of Canada Limited (AECL) in Chalk River, operated a low-dose radiobiology program since as early as 1948. The Canadian Nuclear Laboratories (CNL), the successor to AECL since 2015, has expanded this program into new areas making it the world's most robust, centrally coordinated and long-lived research efforts to delineate the biological effects of low-dose radiation. The purpose of this review is to provide a high-level overview of the low-dose radiobiology program maintained at CNL while capturing the historical perspectives. Past studies carried out at CNL have substantially influenced the area of low-dose radiobiology, exemplified by highly cited papers showing delays in spontaneous tumorigenesis in low-dose irradiated mice. The current low-dose research program at CNL is not only addressing a wide range of mechanistic questions about the biological effects of low doses - from genetic to epigenetic to immunological questions - but also moving toward novel areas, such as the dosimetry and health consequences of space radiation and the use of low-dose radiation in cancer therapy and regenerative medicine.
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http://dx.doi.org/10.1080/09553002.2018.1562252DOI Listing
October 2019

UTX demethylase activity is required for satellite cell-mediated muscle regeneration.

J Clin Invest 2016 Apr 21;126(4):1555-65. Epub 2016 Mar 21.

The X chromosome-encoded histone demethylase UTX (also known as KDM6A) mediates removal of repressive trimethylation of histone H3 lysine 27 (H3K27me3) to establish transcriptionally permissive chromatin. Loss of UTX in female mice is embryonic lethal. Unexpectedly, male UTX-null mice escape embryonic lethality due to expression of UTY, a paralog that lacks H3K27 demethylase activity, suggesting an enzyme-independent role for UTX in development and thereby challenging the need for active H3K27 demethylation in vivo. However, the requirement for active H3K27 demethylation in stem cell-mediated tissue regeneration remains untested. Here, we employed an inducible mouse KO that specifically ablates Utx in satellite cells (SCs) and demonstrated that active H3K27 demethylation is necessary for muscle regeneration. Loss of UTX in SCs blocked myofiber regeneration in both male and female mice. Furthermore, we demonstrated that UTX mediates muscle regeneration through its H3K27 demethylase activity, as loss of demethylase activity either by chemical inhibition or knock-in of demethylase-dead UTX resulted in defective muscle repair. Mechanistically, dissection of the muscle regenerative process revealed that the demethylase activity of UTX is required for expression of the transcription factor myogenin, which in turn drives differentiation of muscle progenitors. Thus, we have identified a critical role for the enzymatic activity of UTX in activating muscle-specific gene expression during myofiber regeneration and have revealed a physiological role for active H3K27 demethylation in vivo.
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http://dx.doi.org/10.1172/JCI83239DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4811158PMC
April 2016

A KAP1 phosphorylation switch controls MyoD function during skeletal muscle differentiation.

Genes Dev 2015 Mar;29(5):513-25

School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne (EPFL), 1015 Lausanne, Switzerland;

The transcriptional activator MyoD serves as a master controller of myogenesis. Often in partnership with Mef2 (myocyte enhancer factor 2), MyoD binds to the promoters of hundreds of muscle genes in proliferating myoblasts yet activates these targets only upon receiving cues that launch differentiation. What regulates this off/on switch of MyoD function has been incompletely understood, although it is known to reflect the action of chromatin modifiers. Here, we identify KAP1 (KRAB [Krüppel-like associated box]-associated protein 1)/TRIM28 (tripartite motif protein 28) as a key regulator of MyoD function. In myoblasts, KAP1 is present with MyoD and Mef2 at many muscle genes, where it acts as a scaffold to recruit not only coactivators such as p300 and LSD1 but also corepressors such as G9a and HDAC1 (histone deacetylase 1), with promoter silencing as the net outcome. Upon differentiation, MSK1-mediated phosphorylation of KAP1 releases the corepressors from the scaffold, unleashing transcriptional activation by MyoD/Mef2 and their positive cofactors. Thus, our results reveal KAP1 as a previously unappreciated interpreter of cell signaling, which modulates the ability of MyoD to drive myogenesis.
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http://dx.doi.org/10.1101/gad.254532.114DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4358404PMC
March 2015

Rbfox proteins regulate tissue-specific alternative splicing of Mef2D required for muscle differentiation.

J Cell Sci 2015 Feb 20;128(4):631-7. Epub 2015 Jan 20.

Dulbecco Telethon Institute and Division of Regenerative Medicine, San Raffaele Scientific Institute, 20132 Milan, Italy

Among the Mef2 family of transcription factors, Mef2D is unique in that it undergoes tissue-specific splicing to generate an isoform that is essential for muscle differentiation. However, the mechanisms mediating this muscle-specific processing of Mef2D remain unknown. Using bioinformatics, we identified Rbfox proteins as putative modulators of Mef2D muscle-specific splicing. Accordingly, we found direct and specific Rbfox1 and Rbfox2 binding to Mef2D pre-mRNA in vivo. Gain- and loss-of-function experiments demonstrated that Rbfox1 and Rbfox2 cooperate in promoting Mef2D splicing and subsequent myogenesis. Thus, our findings reveal a new role for Rbfox proteins in regulating myogenesis through activation of essential muscle-specific splicing events.
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http://dx.doi.org/10.1242/jcs.161059DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4357529PMC
February 2015

Tissue-specific splicing of a ubiquitously expressed transcription factor is essential for muscle differentiation.

Genes Dev 2013 Jun 30;27(11):1247-59. Epub 2013 May 30.

Sprott Center for Stem Cell Research, Ottawa Hospital Research Institute, Ottawa, Ontario K1H 8L6, Canada.

Alternate splicing contributes extensively to cellular complexity by generating protein isoforms with divergent functions. However, the role of alternate isoforms in development remains poorly understood. Mef2 transcription factors are essential transducers of cell signaling that modulate differentiation of many cell types. Among Mef2 family members, Mef2D is unique, as it undergoes tissue-specific splicing to generate a muscle-specific isoform. Since the ubiquitously expressed (Mef2Dα1) and muscle-specific (Mef2Dα2) isoforms of Mef2D are both expressed in muscle, we examined the relative contribution of each Mef2D isoform to differentiation. Using both in vitro and in vivo models, we demonstrate that Mef2D isoforms act antagonistically to modulate differentiation. While chromatin immunoprecipitation (ChIP) sequencing analysis shows that the Mef2D isoforms bind an overlapping set of genes, only Mef2Dα2 activates late muscle transcription. Mechanistically, the differential ability of Mef2D isoforms to activate transcription depends on their susceptibility to phosphorylation by protein kinase A (PKA). Phosphorylation of Mef2Dα1 by PKA provokes its association with corepressors. Conversely, exon switching allows Mef2Dα2 to escape this inhibitory phosphorylation, permitting recruitment of Ash2L for transactivation of muscle genes. Thus, our results reveal a novel mechanism in which a tissue-specific alternate splicing event has evolved that permits a ubiquitously expressed transcription factor to escape inhibitory signaling for temporal regulation of gene expression.
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http://dx.doi.org/10.1101/gad.215400.113DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3690398PMC
June 2013

The origin and fate of muscle satellite cells.

Stem Cell Rev Rep 2012 Jun;8(2):609-22

Sprott Center for Stem Cell Research, Regenerative Medicine Program, Ottawa Hospital Research Institute, 501 Smyth Rd, Mailbox 511, Ottawa, ON, Canada K1H 8L6.

Satellite cells represent the primary population of stem cells resident in skeletal muscle. These adult muscle stem cells facilitate the postnatal growth, remodeling, and regeneration of skeletal muscle. Given the remarkable regenerative potential of satellite cells, there is great promise for treatment of muscle pathologies such as the muscular dystrophies with this cell population. Various protocols have been developed which allow for isolation, enrichment, and expansion of satellite cell derived muscle stem cells. However, isolated satellite cells have yet to translate into effective modalities for therapeutic intervention. Broadening our understanding of satellite cells and their niche requirements should improve our in vivo and ex vivo manipulation of these cells to expedite their use for regeneration of diseased muscle. This review explores the fates of satellite cells as determined by their molecular signatures, ontogeny, and niche dependent programming.
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http://dx.doi.org/10.1007/s12015-012-9352-0DOI Listing
June 2012

MLL5, a trithorax homolog, indirectly regulates H3K4 methylation, represses cyclin A2 expression, and promotes myogenic differentiation.

Proc Natl Acad Sci U S A 2009 Mar 5;106(12):4719-24. Epub 2009 Mar 5.

Centre for Cellular and Molecular Biology, Hyderabad, 500 007 India.

Most cells in adult tissues are nondividing. In skeletal muscle, differentiated myofibers have exited the cell cycle permanently, whereas satellite stem cells withdraw transiently, returning to active proliferation to repair damaged myofibers. We have examined the epigenetic mechanisms operating in conditional quiescence by analyzing the function of a predicted chromatin regulator mixed lineage leukemia 5 (MLL5) in a culture model of reversible arrest. MLL5 is induced in quiescent myoblasts and regulates both the cell cycle and differentiation via a hierarchy of chromatin and transcriptional regulators. Knocking down MLL5 delays entry of quiescent myoblasts into S phase, but hastens S-phase completion. Cyclin A2 (CycA) mRNA is no longer restricted to S phase, but is induced throughout G(0)/G(1), with activation of the cell cycle regulated element (CCRE) in the CycA promoter. Overexpressed MLL5 physically associates with the CCRE and impairs its activity. MLL5 also regulates CycA indirectly: Cux, an activator of CycA promoter and S phase is induced in RNAi cells, and Brm/Brg1, CCRE-binding repressors that promote differentiation are repressed. In knockdown cells, H3K4 methylation at the CCRE is reduced, reflecting quantitative global changes in methylation. MLL5 appears to lack intrinsic histone methyl transferase activity, but regulates expression of histone-modifying enzymes LSD1 and SET7/9, suggesting an indirect mechanism. Finally, expression of muscle regulators Pax7, Myf5, and myogenin is impaired in MLL5 knockdown cells, which are profoundly differentiation defective. Collectively, our results suggest that MLL5 plays an integral role in novel chromatin regulatory mechanisms that suppress inappropriate expression of S-phase-promoting genes and maintain expression of determination genes in quiescent cells.
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http://dx.doi.org/10.1073/pnas.0807136106DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2651835PMC
March 2009