Nuclear receptors connect progenitor transcription factors to cell cycle control

Area of Science:

• Developmental biology
• Molecular genetics
• Cell cycle regulation

Background:

• Organ development relies on transcription factors regulating cell fate and proliferation.
• The precise mechanisms linking transcription factors to the cell cycle remain unclear.
• The developing Drosophila eye serves as a model to study these regulatory networks.

Purpose of the Study:

• To investigate how transcription factors link to cell cycle control in developing organs.
• To elucidate the role of hth and tsh in regulating eye progenitor proliferation.
• To identify the downstream targets and pathways mediating this regulation.

Main Methods:

• Transcriptomics and open-chromatin profiling to identify regulatory elements and target genes.
• Motif analysis to predict transcription factor binding sites.
• Functional assays in Drosophila to validate the roles of hth, tsh, and downstream targets.
• Comparative analysis of homologous gene expression in human cancers.

Main Results:

• The transcription factors hth and tsh synergistically promote the proliferation of naive eye progenitors.
• These factors globally regulate the proliferation program, not by directly targeting cell cycle genes.
• Proliferation is controlled via an intermediary layer involving nuclear receptors of the ecdysone/estrogen-signaling pathway.
• A conserved regulatory subnetwork involving hth, tsh, and nuclear receptors is suggested by co-overexpression in human cancers.

Conclusions:

• Transcription factors hth and tsh coordinate organ growth by linking developmental programs to cell cycle progression.
• The identified regulatory pathway involving nuclear receptors provides a novel mechanism for cell cycle control.
• The conserved nature of this network highlights its potential importance in both development and disease, particularly in cancer.