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Mekhoubad, Shila

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Mekhoubad

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Shila

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Mekhoubad, Shila

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2012 - 20173

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Author's Publications: search.filters.isAuthorOfPublication.737a811f-07ae-444c-9791-56f4f3340cf4

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Now showing 1 - 3 of 3
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    DNA methylation dynamics of the human preimplantation embryo
    (2014) Smith, Zachary; Chan, Michelle M.; Humm, Kathryn C.; Karnik, Rahul; Mekhoubad, Shila; Regev, Aviv; Eggan, Kevin; Meissner, Alexander
    In mammals, cytosine methylation is predominantly restricted to CpG dinucleotides and stably distributed across the genome, with local, cell type-specific regulation directed by DNA binding factors1-3. This comparatively static landscape dramatically contrasts the events of fertilization, where the paternal genome is globally reprogrammed. Paternal genome demethylation includes the majority of CpGs, though methylation is maintained at several notable features4-7. While these dynamics have been extensively characterized in the mouse, only limited observations are available in other mammals, and direct measurements are required to understand the extent to which early embryonic landscapes are conserved8-10. We present genome-scale DNA methylation maps of human preimplantation development and embryonic stem cell (ESC) derivation, confirming a transient state of global hypomethylation that includes most CpGs, while sites of persistent maintenance are primarily restricted to gene bodies. While most features share similar dynamics to mouse, maternally contributed methylation is divergently targeted to species-specific sets of CpG island (CGI) promoters that extend beyond known Imprint Control Regions (ICRs). Retrotransposon regulation is also highly diverse and transitions from maternally to embryonically expressed, species-specific elements. Together, our data confirm that paternal genome demethylation is a general attribute of early mammalian development that is characterized by distinct modes of epigenetic regulation.
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    Erosion of Dosage Compensation Impacts Human iPSC Disease Modeling
    (Elsevier BV, 2012) Mekhoubad, Shila; Bock, Christoph; de Boer, A. Sophie; Kiskinis, Evangelos; Meissner, Alexander; Eggan, Kevin
    Although distinct human induced pluripotent stem cell (hiPSC) lines can display considerable epigenetic variation, it has been unclear whether such variability impacts their utility for disease modeling. Here, we show that although low-passage female hiPSCs retain the inactive X chromosome of the somatic cell they are derived from, over time in culture they undergo an “erosion” of X chromosome inactivation (XCI). This erosion of XCI is characterized by loss of XIST expression and foci of H3-K27-trimethylation, as well as transcriptional derepression of genes on the inactive X that cannot be reversed by either differentiation or further reprogramming. We specifically demonstrate that erosion of XCI has a significant impact on the use of female hiPSCs for modeling Lesch-Nyhan syndrome. However, our finding that most genes subject to XCI are derepressed by this erosion of XCI suggests that it should be a significant consideration when selecting hiPSC lines for modeling any disease.
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    Human pluripotent stem cells recurrently acquire and expand dominant negative P53 mutations
    (Springer Nature, 2017) Merkle, Florian; Ghosh, Sulagna; Kamitaki, Nolan; Mitchell, Jana; Avior, Yishai; Mello, Curtis; Kashin, Seva; Mekhoubad, Shila; Ilic, Dusko; Sweetnam, Maura; Saphier Belfer, Genevieve; Handsaker, Robert; Genovese, Giulio; Bar, Shiran; Benvenisty, Nissim; McCarroll, Steven; Eggan, Kevin
    Background: Depressive disorders are the second-leading cause of global disability, and an area of increasing focus in international health efforts. We describe a community health worker (CHW) program rolled out in a stepped-wedge design during the course of routine patient care to 74 patients with depression in 4 communities in rural Mexico. Methods: We used random effects models to calculate the change in Patient Health Questionnaire-9 (PHQ-9) scores, an internationally validated measure of depression, before and after the CHW program was introduced. As a secondary outcome, we also examined the change pre- and post-intervention in the proportion of patients who had a mean of at least one visit per month for depression follow-up, in accordance with clinic visit guidelines. Results: In multivariate mixed-effects regression, the introduction of the CHW program was associated with a 2.1-point decrease in PHQ-9 score (95% CI: -3.7 to -0.50) followed by a decrease in PHQ-9 score of 0.19 points per month (95% CI: -0.41 to 0.02), beyond standard care. There was strong evidence that patients were far more likely to attend a mean of at least one visit per month (adjusted OR = 8.5, 95% CI: 7.2 to 9.7) after the intervention was introduced in a community. Conclusions: Our results suggest an association between the introduction of a CHW program and improved depression outcomes and appointment adherence. Our findings are limited by missing data. Future research is necessary to develop evidence-based mental health interventions implementable in low-resource settings.