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H3K4 Methylation Controls Vascular Smooth Muscle Cell Lineage Identity and Function

Liu, Mingjun (2022) H3K4 Methylation Controls Vascular Smooth Muscle Cell Lineage Identity and Function. Doctoral Dissertation, University of Pittsburgh. (Unpublished)

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Vascular smooth muscle cells (SMC) are contractile cells regulating blood pressure and vascular homeostasis. Despite the highly specialized functions, SMC retain the plasticity for reversible phenotypic modulation between the contractile state and the “dedifferentiated” state, where SMC lose the expression of specialized contractile genes but acquire enhanced capabilities for proliferation, migration, and synthesis of extracellular matrix. The dynamic phenotypic modulation of SMC has been associated with both adaptive and maladaptive vascular remodeling, depending on whether SMC can efficiently reverse the phenotype back to the contractile state. However, the mechanisms required for SMC to retain its lineage identity during the phenotypic modulation remain unclear. We hypothesized the stable enrichment of H3K4 di-methylation (H3K4me2) on SMC-specific genes functions as an “epigenetic memory” mechanism in maintaining SMC lineage identity and restraining phenotypic plasticity. To study the roles of H3K4me2 enriched on SMC-specific genes, we developed a gene locus-specific H3K4me2 editing tool for selective demethylation of H3K4me2 located on SMC-specific genes without affecting the global H3K4me2 level. By performing selective H3K4me2 editing, we discovered that H3K4me2 is required for SMC contractility, retaining the lineage identity, and restraining plasticity. H3K4me2 is retained during the phenotypic modulation to function as the lineage-specific docking sites to recruit Tet Methylcytosine Dioxygenase 2 (TET2), a master regulator of SMC differentiation by oxidizing methylated DNA on SMC-specific genes. Surprisingly, H3K4me2 is also required for SMC participation in vascular remodeling upon the carotid artery injury through the mechanism of maintaining a low level of miR145, an SMC-specific microRNA, to degrade migration inhibitory genes. Besides, H3K4me2 editing specifically in perivascular cells (SMC and pericytes, SMC-P) reduced SMC-P investment in neo-vessels and impaired microvascular remodeling in response to acute hindlimb ischemia. Loss of H3K4me2 disrupted the SMC-endothelial cell (EC) interaction and permitted SMC acquisition of EC-like morphology in a pro-angiogenesis environment, associated with loss of Notch receptors (Notch1 and Notch2) and downstream transcription factor Hey2. In conclusion, we discovered the stable H3K4me2 enrichment on SMC-specific genes functions as a central epigenetic memory mechanism to maintain the SMC lineage identity and function.


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Item Type: University of Pittsburgh ETD
Status: Unpublished
CreatorsEmailPitt UsernameORCID
Liu, Mingjunmil128@pitt.edumil1280000-0002-8115-3601
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Committee ChairMars, Wendy Mwmars@pitt.eduwmars0000-0003-4495-1054
Thesis AdvisorGomez, Delphinegomezd@pitt.edugomezd0000-0002-3880-6961
Committee MemberChan, Stephenchansy@pitt.educhansy0000-0002-9520-7527
Committee MemberStraub, Adamastraub@pitt.eduastraub0000-0003-0542-9466
Committee MemberRoman, Bethromanb@pitt.eduromanb0000-0002-1250-1705
Date: 28 November 2022
Date Type: Publication
Defense Date: 15 June 2022
Approval Date: 28 November 2022
Submission Date: 8 August 2022
Access Restriction: 1 year -- Restrict access to University of Pittsburgh for a period of 1 year.
Number of Pages: 191
Institution: University of Pittsburgh
Schools and Programs: School of Medicine > Cellular and Molecular Pathology
Degree: PhD - Doctor of Philosophy
Thesis Type: Doctoral Dissertation
Refereed: Yes
Uncontrolled Keywords: Epigenetic priming, lineage memory, Peripheral artery disease, vascular remodeling
Date Deposited: 29 Nov 2022 03:57
Last Modified: 28 Nov 2023 06:15


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