자료유형  

 학위논문

Control Number  

0017163840

International Standard Book Number  

9798346567226

Dewey Decimal Classification Number  

574

Main Entry-Personal Name  

Mauger, MacKenzie.

Publication, Distribution, etc. (Imprint  

[S.l.] : Harvard University., 2024

Publication, Distribution, etc. (Imprint  

Ann Arbor : ProQuest Dissertations & Theses, 2024

Physical Description  

189 p.

General Note  

Source: Dissertations Abstracts International, Volume: 86-05, Section: B.

General Note  

Advisor: Kingston, Robert E.

Dissertation Note  

Thesis (Ph.D.)--Harvard University, 2024.

Summary, Etc.  

요약During development, a single cell gives rise to a complex multicellular organism through establishment and maintenance of cell type-specific gene expression. Polycomb-mediated silencing of lineage inappropriate genes is essential to this process. Knockout of canonical Polycomb Repressive Complex 1 (cPRC1) CBX family paralogs Cbx2 or Cbx4 results in postnatal lethality in mice. This is in contrast to other PcG proteins whose knockout causes early embryonic lethality. Notably, paralogs CBX2, CBX4, and CBX8 share similar domain structure and are co-expressed in differentiated cells. We hypothesize that CBX2, CBX4, and CBX8 are partially redundant while retaining unique functions.CBX2, CBX4, and CBX8 have shared biochemical activities, including nucleosome compaction and condensate formation. To investigate their shared functionality in cells, I utilized an in vitro differentiation system in which mouse embryonic stem cells (mESCs) are differentiated into neural progenitor cells (NPCs). I profiled expression of CBX2, CBX4, and CBX8 throughout differentiation. Expression at the transcript and protein levels shows distinct profiles for CBX2 versus CBX4 and CBX8, suggesting unique roles despite shared biochemical activities.I generated single knockout lines and found that knockout of a single CBX protein resulted in some shared transcriptional changes in NPCs, indicating overlapping function. However, CBX2 knockout caused unique transcriptional changes that signal an earlier arrest in differentiation. I then generated double knockouts, whose transcriptional phenotype was determined by presence or absence of CBX2. Therefore, loss of CBX2 is epistatic to loss of CBX4 or CBX8 during NPC differentiation. These double knockouts did not show a more severe transcriptional phenotype than relevant single knockout lines, so I generated triple knockout lines. Loss of all three paralogs had a morphological phenotype that was not rescued by exogenous expression of CBX2 or of CBX4 and CBX8 although partial transcriptional rescue was observed with exogenous expression of CBX2. Loss of all three paralogs might alter cell state by disrupting Polycomb function in differentiating lineages, providing further evidence of redundancy. In all, we demonstrate that paralogs CBX2 has a unique role in the exit from pluripotency while providing evidence for overlapping roles of CBX2, CBX4, and CBX8 in neural progenitor cell differentiation.

Subject Added Entry-Topical Term  

Biology.

Subject Added Entry-Topical Term  

Cellular biology.

Subject Added Entry-Topical Term  

Molecular biology.

Index Term-Uncontrolled  

CBX paralogs

Index Term-Uncontrolled  

Canonical Polycomb Repressive Complex 1

Index Term-Uncontrolled  

Mouse embryonic stem cells

Added Entry-Corporate Name  

Harvard University Medical Sciences

Host Item Entry  

Dissertations Abstracts International. 86-05B.

Electronic Location and Access  

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Control Number  

joongbu:654828