The chromatin remodeling factor Chd1L in the preimplantation embryo and in ES cells

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Early embryonic cell types such as the zygote, blastomeres of the preimplantation embryo, and embryonic stem (ES) cells have powerful chromatin remodeling activities that facilitate DNA-dependent processes such as transcription and DNA repair. Chd1l encodes a chromatin remodeling factor and is more highly expressed in the inner cell mass (ICM) compared to the whole blastocyst. Chd1l expression is developmentally regulated during a time course of preimplantation development and is present in ES cells. Intriguing expression patterns suggested Chd1l could be a novel regulator of DNA-dependent processes in early developmental cell types. This dissertation describes research undertaken to address the role of Chd1l in chromatin remodeling in the preimplantation embryo and in ES cells. Reducing Chd1l protein to nearly undetectable levels in ES cells reveals that Chd1l is dispensable for ES cell viability, proliferation, and pluripotent morphology. Global gene expression patterns are unaltered by Chd1l knock-down. Chd1l is also dispensable for expression patterns of lineage markers associated with the formation of the primary germ layers in differentiating embryoid bodies. Zygote-stage embryos injected with Chd1l-MO arrest prior to the morula stage. Knock-down by the MO was confirmed at the transcript levels by microfluidic qPCR, and the arrest phenotype was partially rescued upon co-injection of Chd1l mRNA and Chd1l-MO. ES cells are known to have stringent and unique pathways to repair DNA damage to prevent mutation and genomic instability from arising in the organism. Reduction of Chd1l in ES cells confers resistance to induced DNA damage, a finding that contrasts with another study that used a differentiated cell line. Apoptosis induced by over-expression of Chd1l occurs specifically in ES cells and not in their differentiated counterparts. This switch in the effect of Chd1l over-expression during differentiation suggests that the function of Chd1l is very different in ES cells than in differentiated somatic cells. DNA repair through non-homologous end joining (NHEJ) is particularly critical in the zygote to repair the paternal genome. Differentiated somatic cells, but not ES cells also rely heavily on NHEJ. Biochemical evidence supports the involvement of Chd1l in NHEJ. Deficient DNA repair could underlie the Chd1l arrest phenotype. Therefore, Chd1l functions minimally, or not at all, in regulating gene expression and contributes to the DNA damage response in a developmental stage-specific and/or cell type-specific manner.


Type of resource text
Form electronic; electronic resource; remote
Extent 1 online resource.
Publication date 2010
Issuance monographic
Language English


Associated with Snider, Alyssa Christine
Associated with Stanford University, Department of Genetics
Primary advisor Scott, Matthew P
Primary advisor Wysocka, Joanna, Ph. D
Thesis advisor Scott, Matthew P
Thesis advisor Wysocka, Joanna, Ph. D
Thesis advisor Crabtree, Gerald R
Thesis advisor Fuller, Margaret
Thesis advisor Lipsick, Joseph Steven, 1955-
Advisor Crabtree, Gerald R
Advisor Fuller, Margaret
Advisor Lipsick, Joseph Steven, 1955-


Genre Theses

Bibliographic information

Statement of responsibility Alyssa Christine Snider.
Note Submitted to the Department of Genetics.
Thesis Ph.D. Stanford University 2010
Location electronic resource

Access conditions

© 2010 by Alyssa Christine Snider
This work is licensed under a Creative Commons Attribution Non Commercial 3.0 Unported license (CC BY-NC).

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