Single-nucleus multi-omics approaches to enhance musculoskeletal repair Ellen Yujia Zhang

Format:

Book

Thesis/Dissertation

Author/Creator:

Zhang, Ellen Yujia, author.

Contributor:

University of Pennsylvania. Bioengineering., degree granting institution.

Language:

English

Subjects (All):

Bioengineering.

Biomedical engineering.

Physiological psychology.

0202.

0541.

0989.

Local Subjects:

Bioengineering.

Biomedical engineering.

Physiological psychology.

0202.

0541.

0989.

Genre:

Academic theses

Physical Description:

1 online resource (169 pages)

Contained In:

Dissertations Abstracts International 87-12B

Place of Publication:

Ann Arbor : ProQuest Dissertations and Theses, 2026

Language Note:

English

Summary:

Connective tissue cells-including chondrocytes, tenocytes, and mesenchymal progenitors-depend on precisely maintained gene expression programs to fulfill their structural and mechanical roles, yet these programs are fragile: they are actively sustained by the chromatin landscape of the cell and are susceptible to dysregulation by mechanical, biochemical, and genetic perturbations. When cell identity is lost or misdirected, the consequences include impaired cartilage repair, pathological heterotopic ossification, and age-related tendon degeneration. This dissertation investigates the chromatin-level mechanisms by which environmental signals produce stable changes in connective tissue cell identity across three distinct biological contexts: chondrocyte dedifferentiation during in vitro expansion, aberrant osteogenic fate commitment in fibrodysplasia ossificans progressiva (FOP), and tenocyte maturation during Achilles tendon development. To address these questions, a complementary suite of approaches was employed, including single-nucleus multiome sequencing (snMultiome), super-resolution stochastic optical reconstruction microscopy (STORM), assay for transposase-accessible chromatin sequencing (ATAC-Seq), bulk RNA sequencing (RNA-Seq), and chromatin immunoprecipitation sequencing (ChIP-Seq) for H3K4me3 and H3K27me3, applied to human articular chondrocytes, murine embryonic fibroblasts carrying the FOP-associated ACVR1R206H mutation, and developmental and mature murine tenocytes. In the chondrocyte system, snMultiome revealed that dedifferentiation involves coordinated remodeling of both the transcriptome and the chromatin accessibility landscape, enabling identification of STAT1 as a transcription factor driving epigenetic remodeling of chondrocyte identity; pharmacological STAT1 inhibition with Fludarabine preserved chondrogenic phenotype through active epigenetic reprogramming. In FOP, hyperactive BMP/SMAD and Rho/ROCK mechanosignaling convergently drove global chromatin decondensation and enhanced accessibility at osteogenic regulatory elements, and pharmacological inhibition of either pathway restored chromatin organization to wild-type levels. In tenocytes, maturation was associated with increased chromatin condensation and a two-arm histone modification program in which H3K4me3 enrichment at contractility and ECM genes reinforces the mechanobiological demands of mature tendon, while H3K27me3 deposition at disease-associated loci suppresses aberrant gene activation. Together, these findings establish chromatin organization and epigenetic state as central mediators of connective tissue cell identity and as actionable targets for preserving, restoring, and understanding cell phenotype in the context of disease and repair

Notes:

Source: Dissertations Abstracts International, Volume: 87-12, Section: B.

Advisors: Heo, Su Chin Committee members: Mauck, Robert L.; Lakadamyali, Melike; Kim, Dokyoon; Jung, Inkyung

Ph.D. University of Pennsylvania 2026

Vendor supplied data

Local Notes:

School code: 0175

ISBN:

9798247980087

Access Restriction:

Restricted for use by site license