RNAseq analysis of heart samples collected from wild-type and ZNF768 null mice 8 hours post-irradiation

Cell proliferation is a fundamental process required for organismal
development, growth, and maintenance. Failure to control this process
leads to several diseases, including cancer. Zinc finger protein 768
(ZNF768) is an emerging transcription factor that plays key roles in
driving proliferation. In addition to controlling a gene network
supporting cell division, ZNF768 physically interacts and inhibits the
activity of the tumor suppressor p53. Although the importance of ZNF768 in
promoting cell proliferation has been well demonstrated in vitro,
the physiological and pathological roles of ZNF768 in
vivo are still unknown. Here, we report the generation and
characterization of a ZNF768 null mouse model. ZNF768 null mice are viable
but show a growth defect early in life. Mouse embryonic fibroblasts (MEFs)
isolated from ZNF768 null embryos exhibit higher p53 levels, premature
senescence, and higher sensitivity to genotoxic stress. In line with these
findings, ZNF768 null mice showed increased
radiosensitivity. This effect was associated not only with higher
expression of a subset of p53 targets genes, but also with alterations in
genes regulating transmembrane receptor signaling, cell adhesion, and
growth. Because ZNF768 levels are elevated in tumors, we tested
the impact of ZNF768 loss on cancer development in mice. Here, we show
that ZNF768 deletion was sufficient to repress lung tumor development in a
KRASG12D-induced cancer mouse model. Overall, our findings establish
ZNF768 as an important protein controlling cell proliferation that could
potentially be targeted to reduce tumorigenesis.