This review examines the molecular mechanisms controlling the development and homeostasis of the musculoskeletal system through gene expression regulation. It introduces key discoveries from basic transcriptional control to advanced mechanotransduction pathways, focusing on our contributions including the EMBRYS database for transcription factor expression analysis and the identification of RP58 in muscle development and Mohawk (Mkx) in tendon formation. We also elucidated the role of miR-140 as a critical regulator in cartilage development and homeostasis. This microRNA is specifically expressed in cartilage, promotes chondrogenesis, and is involved in protective mechanisms against cartilage degenerative diseases such as osteoarthritis. Our discovery of the PIEZO1-Mkx pathway provides a molecular mechanism linking mechanical stimuli to gene expression in tendons, explaining tissue adaptation and differences in motor abilities. Understanding these pathways offers new therapeutic strategies for tendon and ligament injuries, age-related decline, and cartilage diseases. Currently, we are proposing the concept of “tenopenia” to complement sarcopenia, addressing the mechanisms of age-related tendon deterioration. This integrated approach to the musculoskeletal system as an environment-responsive entity advances both fundamental science and clinical applications aimed at maintaining mobility throughout life.

Mechanical stress activates the Piezo1 channel in tendon cells, leading to calcium influx and subsequent activation of the transcription factor Mkx. This Piezo1–Mkx axis promotes tendon development and supports locomotor function. Genetic polymorphisms in Piezo1 may modulate this pathway in both mice and humans.

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The term “clone” is commonly used in the medical and life sciences to denote a genetically identical population, at both the individual and cellular levels. The concept of clonal expansion is of fundamental importance in cancer research. The advent of advanced sequencing technologies has elucidated the clonal nature of intermediates between normal cells and cancer cells. This review underscores seminal discoveries in the blood and stratified squamous epithelial systems, emphasizing the pivotal role of mutations in DNA modifier genes and Notch pathway genes, respectively, as drivers of clonal expansion. Despite the distinct nature of these systems and their genetic backgrounds, a common biological principle emerges.

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Transcription is an essential biological process that underlies all cellular and organismal activities. In eukaryotes, RNA polymerase II (RNAPII) transcribes every protein-coding gene and many non-coding genes, playing a central role in gene expression. Transcription generally occurs in three steps: RNAPII initiates transcription from a gene promoter, elongates RNA as it traverses the gene body, and terminates transcription at the end of the gene. Dynamic interactions with multiple accessory factors allow RNAPII to form functional transcription complexes and accomplish these processes in chromatin. Recent progress in structural biology has illuminated the structural and mechanistic details of RNAPII functions, particularly promoter-proximal pausing, nucleosome transcription, and transcription termination. This review provides a survey of these advances and discusses future directions.

During transcription, RNA polymerase II dynamically interacts with various accessory factors to form diverse functional transcription complexes. These complexes facilitate transcription in chromatin and accomplish multiple transcription-related functions to support cellular activities.

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Renal counterbalance, involving compensatory hypertrophy of the healthy kidney and atrophy of the injured one, remains incompletely understood, particularly at the glomerular level. In this study, we employed NEP25 mice, which selectively express human CD25 in podocytes, enabling precise induction of unilateral podocyte injury through the administration of LMB2, a CD25-targeted immunotoxin. Using a two-kidney, one-nephropathy (2K1N) model, we demonstrated that asymmetric changes in renal blood flow and proteinuria, with histological and transcriptomic analyses uncovering distinct pathological and molecular features between the injured and contralateral healthy kidneys. Notably, an imbalance in intrarenal angiotensin (Ang) II levels was observed, and angiotensin-converting enzyme inhibition ameliorated the glomerular damage and restored perfusion. These findings indicate that local Ang II dysregulation is a key factor in renal counterbalance. Our study provides the first glomerulopathy-based experimental platform to dissect asymmetric renal adaptation, offering fundamental insight into the homeostatic mechanisms of renal function in health and disease.

In transgenic NEP25 mice expressing human CD25 in podocytes, two kidney transplantation models were established to investigate renal counterbalance. The 2K1N model involved transplantation of a wild-type kidney, while the 2K2N model involved transplantation of another CD25-expressing kidney. Podocyte injury was induced by administration of the anti-human CD25 immunotoxin LMB2, resulting in glomerular damage. In the 2K1N model, asymmetric podocyte injury led to compensatory hypertrophy and functional preservation in the healthy kidney, whereas the injured kidney developed glomerular sclerosis. This imbalance was associated with local overproduction of angiotensin II in the injured kidney, contributing to renal counterbalance failure and hemodynamic dysregulation.

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