The transcription factor Hey and nuclear lamins specify and maintain cell identity

Abstract

The inability of differentiated cells to maintain their identity is a hallmark of age-related diseases. We found that the transcription factor Hey supervises the identity of differentiated enterocytes (ECs) in the adult Drosophila midgut. Lineage tracing established that Hey-deficient ECs are unable to maintain their unique nuclear organization and identity. To supervise cell identity, Hey determines the expression of nuclear lamins, switching from a stem-cell lamin configuration to a differentiated lamin configuration. Moreover, continued Hey expression is required to conserve large-scale nuclear organization. During aging, Hey levels decline, and EC identity and gut homeostasis are impaired, including pathological reprograming and compromised gut integrity. These phenotypes are highly similar to those observed upon acute targeting of Hey or perturbation of lamin expression in ECs in young adults. Indeed, aging phenotypes were suppressed by continued expression of Hey in ECs, suggesting that a Hey-lamin network safeguards nuclear organization and differentiated cell identity.

Organelle size scaling over embryonic development

“…Nuclear import and lamins also control nuclear size in C. elegans (Ladouceur, Dorn, & Maddox, 2015;Meyerzon et al, 2009). Given that NPCs and lamins exhibit age-dependent deterioration, changes in import capacity could contribute to altered nuclear morphology in aging cells (H. Chen, Zheng, & Zheng, 2014;D'Angelo, Raices, Panowski, & Hetzer, 2009;Flint Brodsly et al, 2019;Frost, Bardai, & Feany, 2016;Toyama et al, 2019). Caenorhabditis elegans worm data are from .…”

Longevity strategies in response to light in the reef coral Stylophora pistillata

“…Consistent with our data, the closely related HELT in Nematostella vectensis exhibits light-dependent oscillating expression 40 . A HEY family of TFs was recently associated with the maintenance of stem cell functional pools through p53 or lamin regulation in mice and Drosophila 50,51 and with cancer cell self-renewal and differentiation in humans, which suggests that it may contribute to cell renewal homeostasis in physiological and aging contexts. PTHD3 belongs to the Patched Domain-Containing gene family, which is ancient in animal and plant evolution 52 .…”

Structure-Function Relationships of Nuclear Lamins

“…Additionally, a candidate gene locus ZNF570 repositioned away from the nuclear lamina in lamin B2 depleted cells, which correlated with a significant increase in its transcript levels [97]. Lamin C (LamC, D. melanogaster A-type lamin) and the transcription factor Hey partner to maintain nuclear architecture unique to differentiated enterocytes (ECs), as loss of Hey or aberrant lamin expression shows loss of EC identity [134]. Interestingly, transcriptionally active chromatin can also associate with lamin B1, forming dynamic euchromatin-lamin B1-associated domains in murine cells [135].…”