Ancestry-dependent gene expression correlates with reprogramming to pluripotency and multiple dynamic biological processes

Abstract

Induced pluripotent stem cells (iPSCs) can be derived from differentiated cells, enabling the generation of personalized disease models by differentiating patient-derived iPSCs into disease-relevant cell lines. While genetic variability between different iPSC lines affects differentiation potential, how this variability in somatic cells affects pluripotent potential is less understood. We generated and compared transcriptomic data from 72 dermal fibroblast–iPSC pairs with consistent variation in reprogramming efficiency. By considering equal numbers of samples from self-reported African Americans and White Americans, we identified both ancestry-dependent and ancestry-independent transcripts associated with reprogramming efficiency, suggesting that transcriptomic heterogeneity can substantially affect reprogramming. Moreover, reprogramming efficiency–associated genes are involved in diverse dynamic biological processes, including cancer and wound healing, and are predictive of 5-year breast cancer survival in an independent cohort. Candidate genes may provide insight into mechanisms of ancestry-dependent regulation of cell fate transitions and motivate additional studies for improvement of reprogramming.

Power and optimal study design in iPSC-based brain disease modelling

“…Case-control study designs (Design 1) are suited for this purpose, yet the clustering of data points introduced by obtaining multiple measurements from different genetically heterogeneous individuals has a considerable impact on the attainable statistical power. Previously, gene expression studies indicated that donorspecific differences account for a considerable proportion of the overall variability [21,[28][29][30][31][32][33][34]. Consequently, several studies conclude that iPSC-based studies benefit from including more donors, rather than more clonal iPSC lines from the same individual [21,22,29,31,35,36].…”

Chronic stress-driven glucocorticoid receptor activation programs key cell phenotypes and functional epigenomic patterns in human fibroblasts

“…IMR-90 (human fetal lung fibroblast) cells were obtained from the Coriell Institute for Medical Research and authenticated using Short Tandem Repeat (STR) analysis ( Capes-Davis et al., 2013 , American Type Culture Collection Standards Development Organization Workgroup et al., 2011 ). Primary dermal fibroblasts (White female, age 21; White male, age 21; Black female, age 21; Black male, age 22) are derived from an established cohort of previously characterized primary dermal fibroblasts at the National Institute of Environmental Health Sciences ( Mackey et al., 2018 ; Bisogno et al., 2020 ). Both IMR-90 and dermal fibroblasts were maintained in Dulbecco’s Modified Eagle Medium (DMEM) without phenol red and supplemented with 15% fetal bovine serum (FBS), high glucose, L-glutamine, sodium pyruvate, non-essential amino acids, and Antibiotic-Antimycotic.…”

“…Detailed methods are provided in the online version of this paper and include the following: (Mackey et al, 2018;Bisogno et al, 2020). Both IMR-90 and dermal fibroblasts were maintained in Dulbecco's Modified Eagle Medium (DMEM) without phenol red and supplemented with 15% fetal bovine serum (FBS), high glucose, L-glutamine, sodium pyruvate, non-essential amino acids, and Antibiotic-Antimycotic.…”

The Future of Gene Therapy for Transfusion-Dependent Beta-Thalassemia: The Power of the Lentiviral Vector for Genetically Modified Hematopoietic Stem Cells

“…iPSCs are autologous somatic cells that are reprogrammed into an embryonic-like stage in vitro. Two key features of human iPSCs are the capacity for self-renewal and pluripotency, which is the ability to differentiate into all cell types (Takahashi and Yamanaka, 2006;Yu et al, 2007), including HSCs (Bisogno et al, 2020;Demirci et al, 2020). Therefore, human iPSCs derived from patients are an attractive cell source for the development of novel strategies for the treatment of hematological disorders (Donada et al, 2020;Kennedy et al, 2012) (Figure 2A).…”