Liu, Mingjun
(2022)
H3K4 Methylation Controls Vascular Smooth Muscle Cell Lineage Identity and Function.
Doctoral Dissertation, University of Pittsburgh.
(Unpublished)
Abstract
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.
Share
| Citation/Export: |
|
| Social Networking: |
|
Details
| Item Type: |
University of Pittsburgh ETD
|
| Status: |
Unpublished |
| Creators/Authors: |
|
| ETD Committee: |
|
| 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 |
| URI: |
http://d-scholarship.pitt.edu/id/eprint/43331 |
Metrics
Monthly Views for the past 3 years
Plum Analytics
Actions (login required)
 |
View Item |
![[feed]](/images/feed-icon-32x32.png){kind=icon}