Local Genome Topology Can Exhibit an Incompletely Rewired 3D-Folding State during Somatic Cell Reprogramming
Name:
Publisher version
View Source
Access full-text PDFOpen Access
View Source
Check access options
Check access options
Authors
Beagan, Jonathan A.Gilgenast, Thomas G.
Kim, Jesi
Plona, Zachary
Norton, Heidi K.
Hu, Gui
Hsu, Sarah C.
Shields, Emily J.
Lyu, Xiaowen
Apostolou, Effie
Hochedlinger, Konrad
Corces, Victor G.
Dekker, Job
Phillips-Cremins, Jennifer E.
UMass Chan Affiliations
Department of Biochemistry and Molecular PharmacologyProgram in Systems Biology
Document Type
Journal ArticlePublication Date
2016-05-05Keywords
Cell BiologyComputational Biology
Developmental Biology
Genetics
Genomics
Molecular Biology
Structural Biology
Systems Biology
Metadata
Show full item recordAbstract
Pluripotent genomes are folded in a topological hierarchy that reorganizes during differentiation. The extent to which chromatin architecture is reconfigured during somatic cell reprogramming is poorly understood. Here we integrate fine-resolution architecture maps with epigenetic marks and gene expression in embryonic stem cells (ESCs), neural progenitor cells (NPCs), and NPC-derived induced pluripotent stem cells (iPSCs). We find that most pluripotency genes reconnect to target enhancers during reprogramming. Unexpectedly, some NPC interactions around pluripotency genes persist in our iPSC clone. Pluripotency genes engaged in both "fully-reprogrammed" and "persistent-NPC" interactions exhibit over/undershooting of target expression levels in iPSCs. Additionally, we identify a subset of "poorly reprogrammed" interactions that do not reconnect in iPSCs and display only partially recovered, ESC-specific CTCF occupancy. 2i/LIF can abrogate persistent-NPC interactions, recover poorly reprogrammed interactions, reinstate CTCF occupancy, and restore expression levels. Our results demonstrate that iPSC genomes can exhibit imperfectly rewired 3D-folding linked to inaccurately reprogrammed gene expression.Source
Cell Stem Cell. 2016 May 5;18(5):611-24. doi: 10.1016/j.stem.2016.04.004. Link to article on publisher's siteDOI
10.1016/j.stem.2016.04.004Permanent Link to this Item
http://hdl.handle.net/20.500.14038/49969PubMed ID
27152443Related Resources
Link to Article in PubMedae974a485f413a2113503eed53cd6c53
10.1016/j.stem.2016.04.004
Scopus Count
Collections
Related items
Showing items related by title, author, creator and subject.
-
Mapping and analysis of Caenorhabditis elegans transcription factor sequence specificitiesNarasimhan, Kamesh; Lambert, Samuel A.; Yang, Ally; Riddell, Jeremy; Mnaimneh, Sanie; Zheng, Hong; Albu, Mihai; Najafabadi, Hamed S.; Reece-Hoyes, John S.; Fuxman Bass, Juan; et al. (2015-04-23)Caenorhabditis elegans is a powerful model for studying gene regulation, as it has a compact genome and a wealth of genomic tools. However, identification of regulatory elements has been limited, as DNA-binding motifs are known for only 71 of the estimated 763 sequence-specific transcription factors (TFs). To address this problem, we performed protein binding microarray experiments on representatives of canonical TF families in C. elegans, obtaining motifs for 129 TFs. Additionally, we predict motifs for many TFs that have DNA-binding domains similar to those already characterized, increasing coverage of binding specificities to 292 C. elegans TFs (~40%). These data highlight the diversification of binding motifs for the nuclear hormone receptor and C2H2 zinc finger families, and reveal unexpected diversity of motifs for T-box and DM families. Motif enrichment in promoters of functionally related genes is consistent with known biology, and also identifies putative regulatory roles for unstudied TFs.
-
Combined experimental and computational analysis of DNA damage signaling reveals context-dependent roles for Erk in apoptosis and G1/S arrest after genotoxic stressTentner, Andrea R.; Lee, Michael J.; Ostheimer, Gerry J.; Samson, Leona D.; Lauffenburger, Douglas A.; Yaffe, Michael B. (2012-01-31)Following DNA damage, cells display complex multi-pathway signaling dynamics that connect cell-cycle arrest and DNA repair in G1, S, or G2/M phase with phenotypic fate decisions made between survival, cell-cycle re-entry and proliferation, permanent cell-cycle arrest, or cell death. How these phenotypic fate decisions are determined remains poorly understood, but must derive from integrating genotoxic stress signals together with inputs from the local microenvironment. To investigate this in a systematic manner, we undertook a quantitative time-resolved cell signaling and phenotypic response study in U2OS cells receiving doxorubicin-induced DNA damage in the presence or absence of TNFalpha co-treatment; we measured key nodes in a broad set of DNA damage signal transduction pathways along with apoptotic death and cell-cycle regulatory responses. Two relational modeling approaches were then used to identify network-level relationships between signals and cell phenotypic events: a partial least squares regression approach and a complementary new technique which we term 'time-interval stepwise regression.' Taken together, the results from these analysis methods revealed complex, cytokine-modulated inter-relationships among multiple signaling pathways following DNA damage, and identified an unexpected context-dependent role for Erk in both G1/S arrest and apoptotic cell death following treatment with this commonly used clinical chemotherapeutic drug.
-
The genome-wide multi-layered architecture of chromosome pairing in early Drosophila embryosErceg, Jelena; AlHaj Abed, Jumana; Goloborodko, Anton; Lajoie, Bryan R.; Fudenberg, Geoffrey; Abdennur, Nezar; Imakaev, Maxim; McCole, Ruth B.; Nguyen, Son C.; Saylor, Wren; et al. (2019-10-03)Genome organization involves cis and trans chromosomal interactions, both implicated in gene regulation, development, and disease. Here, we focus on trans interactions in Drosophila, where homologous chromosomes are paired in somatic cells from embryogenesis through adulthood. We first address long-standing questions regarding the structure of embryonic homolog pairing and, to this end, develop a haplotype-resolved Hi-C approach to minimize homolog misassignment and thus robustly distinguish trans-homolog from cis contacts. This computational approach, which we call Ohm, reveals pairing to be surprisingly structured genome-wide, with trans-homolog domains, compartments, and interaction peaks, many coinciding with analogous cis features. We also find a significant genome-wide correlation between pairing, transcription during zygotic genome activation, and binding of the pioneer factor Zelda. Our findings reveal a complex, highly structured organization underlying homolog pairing, first discovered a century ago in Drosophila. Finally, we demonstrate the versatility of our haplotype-resolved approach by applying it to mammalian embryos.