(FK131946) Támogató: Nemzeti Kutatási, Fejlesztési és Innovációs Hivatal
DNA methylation, catalyzed by DNA methyltransferases (DNMT), plays pivotal role in
regulating embryonic development, gene expression, adaption to environmental stress,
and maintaining genome integrity. DNMT family consists of DNMT1, DNMT3A, DNMT3B, and
the enzymatically inactive DNMT3L. DNMT3A and DNMT3B establish novel methylation patterns
maintained by DNMT1 during replication. Genetic variants of DNMT3A and DNMT3B cause
rare diseases such as Tatton-Brown-Rahman and ICF syndromes. Additionally, somatic
mutations cause common conditions such as osteoarthritis, osteoporosis, clonal hematopoiesis
of indeterminate potential (CHIP), hematologic malignancies, and cancer. While DNMTs
have been extensively studied in vitro, in early development and in disease, their
detailed physiologic roles remain less understood as in vivo investigations are hindered
by the embryonic or perinatal lethality of the knockout mice. To circumvent this problem,
tissue-specific Dnmt3a and Dnmt3b knockouts were engineered. This review explores
their diverse molecular roles across various organs and cell types and characterizes
the phenotype of the knockout mice. We provide a comprehensive collection of over
forty tissue-specific knockout models generated by cre recombinase. We highlight the
distinct functions of DNMT3A and DNMT3B in germ cells, early development, uterus,
hematopoietic differentiation, musculoskeletal development, visceral organs, and nervous
system. Our findings indicate that DNMT3A primarily regulates hematopoietic differentiation,
while DNMT3B is crucial for cartilage homeostasis and ossification. We emphasize the
context-dependent roles of DNMT3A and DNMT3B and demonstrate that they also complement
DNMT1 maintenance methyltransferase activity. Overall, the expression patterns of
DNMTs across tissues provide insights into potential therapeutic applications for
treating neurologic diseases, cancer, and osteoporosis.
