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Roles of Euchromatin and Heterochromatin in Hepatocyte Maturation and Liver Fibrosis Jessica Mae Grindheim University of Pennsylvania, [email protected]

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Roles of Euchromatin and Heterochromatin in Hepatocyte Maturation and Liver Fibrosis Jessica Mae Grindheim University of Pennsylvania, Jmgrindheim@Gmail.Com University of Pennsylvania ScholarlyCommons Publicly Accessible Penn Dissertations 2019 Roles Of Euchromatin And Heterochromatin In Hepatocyte Maturation And Liver Fibrosis Jessica Mae Grindheim University of Pennsylvania, [email protected] Follow this and additional works at: https://repository.upenn.edu/edissertations Part of the Cell Biology Commons, and the Developmental Biology Commons Recommended Citation Grindheim, Jessica Mae, "Roles Of Euchromatin And Heterochromatin In Hepatocyte Maturation And Liver Fibrosis" (2019). Publicly Accessible Penn Dissertations. 3258. https://repository.upenn.edu/edissertations/3258 This paper is posted at ScholarlyCommons. https://repository.upenn.edu/edissertations/3258 For more information, please contact [email protected]. Roles Of Euchromatin And Heterochromatin In Hepatocyte Maturation And Liver Fibrosis Abstract Liver transplantation is the main treatment for acute liver failure patients; however, there is an insufficient supply of donor livers. Since transplanting hepatocytes, the main liver cell type, provides therapeutic effect and can be a bridge to transplant or recovery, scientists are working on generating replacement hepatocytes from stem cells and other cell types through reprogramming protocols. Currently, replacement hepatocytes recapitulate a subset of natural hepatocyte features, yet are still in an immature state, as they have not silenced all immature hepatocyte genes and activated all mature hepatocyte genes. Consequently, replacement hepatocytes do not perform as well as natural hepatocytes in transplant experiments. Despite these shortcomings, relatively little is known about how natural hepatic maturation is regulated, particularly at the chromatin level. We discovered extensive chromatin dynamics during hepatic postnatal maturation, including changes in H3K9me3-marked and H3K27me3-marked heterochromatin, and transcription. Heterochromatin is of particular interest, as we found that it guards cell identity by repressing lineage-inappropriate or temporally- inappropriate genes. We further classified H3K9me3- and H3K27me3-marked chromatin by compaction state with a novel assay, termed srHC-seq. In postnatal hepatocyte maturation H3K27me3-marked heterochromatin represses early maturation genes, late maturation genes, and alternative lineage genes to both regulate timing of hepatic maturation and repress alternate fates. Significantly, we identify a euchromatic H3K27me3+ promoter signature that predicts which H3K27me3-marked genes will derepress in response ablation of the enzymes that deposit H3K27me3. Disruption of either H3K9me3- or H3K27me3-marked chromatin leads to liver damage, and in the case of H3K27me3 this is likely due to the aberrant derepression of genes associated with fibrosis that normally have a euchromatic H3K27me3+ promoter signature. Our results emphasize the role of heterochromatin in regulating liver development, maturation, and fibrosis, and highlight the need to identify factors controlling heterochromatin formation and breakdown, both for the purposes of enhancing in vitro hepatic maturation and for understanding factors which predispose humans to disease. Degree Type Dissertation Degree Name Doctor of Philosophy (PhD) Graduate Group Cell & Molecular Biology First Advisor Kenneth S. Zaret This dissertation is available at ScholarlyCommons: https://repository.upenn.edu/edissertations/3258 Keywords chromatin, hepatocyte, liver, maturation Subject Categories Cell Biology | Developmental Biology This dissertation is available at ScholarlyCommons: https://repository.upenn.edu/edissertations/3258 ROLES OF EUCHROMATIN AND HETEROCHROMATIN IN HEPATOCYTE MATURATION AND LIVER FIBROSIS Jessica Mae Grindheim A DISSERTATION in Cell and Molecular Biology Presented to the Faculties of the University of Pennsylvania in Partial Fulfillment of the Requirements for the Degree of Doctor of Philosophy 2019 Supervisor of Dissertation ________________________________ Kenneth S. Zaret, Ph.D. Joseph Leidy Professor of Cell and Developmental Biology Graduate Group Chairperson ________________________________ Daniel S. Kessler, Ph.D. Associate Professor of Cell and Developmental Biology Dissertation Committee Ben Z. Stanger, M.D., Ph.D., Professor of Medicine Stephen A. Liebhaber, MD, Professor of Genetics Paul J Gadue, Ph.D., Associate Professor of Pathology and Laboratory Medicine Maya Capelson, Ph.D., Assistant Professor of Cell and Developmental Biology ROLES OF EUCHROMATIN AND HETEROCHROMATIN IN HEPATOCYTE MATURATION AND LIVER FIBROSIS COPYRIGHT 2019 Jessica Mae Grindheim ABSTRACT REGULATION OF HEPATIC DEVELOPMENT AND MATURATION BY TWO CLASSES OF HETEROCHROMATIN Jessica Mae Grindheim Kenneth S Zaret Liver transplantation is the main treatment for acute liver failure patients; however, there is an insufficient supply of donor livers. Since transplanting hepatocytes, the main liver cell type, provides therapeutic effect and can be a bridge to transplant or recovery, scientists are working on generating replacement hepatocytes from stem cells and other cell types through reprogramming protocols. Currently, replacement hepatocytes recapitulate a subset of natural hepatocyte features, yet are still in an immature state, as they have not silenced all immature hepatocyte genes and activated all mature hepatocyte genes. Consequently, replacement hepatocytes do not perform as well as natural hepatocytes in transplant experiments. Despite these shortcomings, relatively little is known about how natural hepatic maturation is regulated, particularly at the chromatin level. We discovered extensive chromatin dynamics during hepatic postnatal maturation, including changes in H3K9me3-marked and H3K27me3-marked heterochromatin, and transcription. Heterochromatin is of particular interest, as we found that it guards cell identity by repressing lineage-inappropriate or temporally-inappropriate genes. We further classified H3K9me3- and H3K27me3-marked chromatin by compaction state with a novel iii assay, termed srHC-seq. In postnatal hepatocyte maturation H3K27me3-marked heterochromatin represses early maturation genes, late maturation genes, and alternative lineage genes to both regulate timing of hepatic maturation and repress alternate fates. Significantly, we identify a euchromatic H3K27me3+ promoter signature that predicts which H3K27me3-marked genes will derepress in response ablation of the enzymes that deposit H3K27me3. Disruption of either H3K9me3- or H3K27me3-marked chromatin leads to liver damage, and in the case of H3K27me3 this is likely due to the aberrant derepression of genes associated with fibrosis that normally have a euchromatic H3K27me3+ promoter signature. Our results emphasize the role of heterochromatin in regulating liver development, maturation, and fibrosis, and highlight the need to identify factors controlling heterochromatin formation and breakdown, both for the purposes of enhancing in vitro hepatic maturation and for understanding factors which predispose humans to disease. iv Table of Contents ABSTRACT ................................................................................................................................ iii Table of Contents .................................................................................................................... v Chapter 1: Introduction ......................................................................................................... 1 1.1. A clinical need for new sources of human hepatocytes ...................................................... 1 1.2. Lack of terminal maturation in artificially generated hepatocytes .................................... 2 1.3. Regulation of postnatal hepatic maturation ............................................................................ 5 1.4. Guarding cell identity with Polycomb-marked chromatin ................................................... 8 1.5. Polycomb repression in endoderm lineage development ................................................. 19 1.6. Figures ............................................................................................................................................. 21 Figure 1: Liver transplant survival and demand in the US .............................................................. 21 Figure 2: PRC1 and 2 complexes ....................................................................................................... 22 Figure 3: Multiple mechanisms of PcG repression .......................................................................... 24 1.7. Tables ............................................................................................................................................... 25 1.8. References ...................................................................................................................................... 26 Chapter 2: PRC2 proteins EZH1/2 regulate timely postnatal hepatocyte maturation and fibrosis by repression of euchromatic promoters .....37 2.1. Preface ............................................................................................................................................. 37 2.2. Respective Contributions ........................................................................................................... 38 2.3. Abstract ........................................................................................................................................... 39 2.4. Graphical abstract .......................................................................................................................
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