UTX coordinates steroid hormone-mediated autophagy and cell death

Donna Denton; May T Aung-Htut; Nirmal Lorensuhewa; Shannon Nicolson; Wenying Zhu; Kathryn Mills; Dimitrios Cakouros; Andreas Bergmann; Sharad Kumar

doi:10.1038/ncomms3916

UTX coordinates steroid hormone-mediated autophagy and cell death

Nat Commun. 2013:4:2916. doi: 10.1038/ncomms3916.

Authors

Donna Denton¹, May T Aung-Htut², Nirmal Lorensuhewa², Shannon Nicolson², Wenying Zhu², Kathryn Mills², Dimitrios Cakouros², Andreas Bergmann³, Sharad Kumar⁴

Affiliations

¹ 1] Centre for Cancer Biology, SA Pathology, Frome Road, Adelaide, South Australia 5000, Australia [2] Division of Health Sciences, University of South Australia, Adelaide, South Australia 5001, Australia.
² Centre for Cancer Biology, SA Pathology, Frome Road, Adelaide, South Australia 5000, Australia.
³ Department of Cancer Biology, University of Massachusetts Medical School, Worcester, Massachusetts 01605, USA.
⁴ 1] Centre for Cancer Biology, SA Pathology, Frome Road, Adelaide, South Australia 5000, Australia [2] Division of Health Sciences, University of South Australia, Adelaide, South Australia 5001, Australia [3] Department of Medicine, The University of Adelaide, Adelaide, South Australia 5005, Australia.

Abstract

Correct spatial and temporal induction of numerous cell type-specific genes during development requires regulated removal of the repressive histone H3 lysine 27 trimethylation (H3K27me3) modification. Here we show that the H3K27me3 demethylase dUTX is required for hormone-mediated transcriptional regulation of apoptosis and autophagy genes during ecdysone-regulated programmed cell death of Drosophila salivary glands. We demonstrate that dUTX binds to the nuclear hormone receptor complex Ecdysone Receptor/Ultraspiracle, and is recruited to the promoters of key apoptosis and autophagy genes. Salivary gland cell death is delayed in dUTX mutants, with reduced caspase activity and autophagy that coincides with decreased apoptosis and autophagy gene transcripts. We further show that salivary gland degradation requires dUTX catalytic activity. Our findings provide evidence for an unanticipated role for UTX demethylase activity in regulating hormone-dependent cell death and demonstrate how a single transcriptional regulator can modulate a specific complex functional outcome during animal development.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Animals
Apoptosis / genetics
Autophagy / genetics*
Caspases / genetics
Caspases / metabolism
Cell Death / drug effects
Cell Death / genetics
DNA-Binding Proteins / genetics
DNA-Binding Proteins / metabolism
Drosophila / cytology
Drosophila / genetics
Drosophila Proteins / genetics
Drosophila Proteins / metabolism*
Ecdysone / metabolism*
Ecdysone / pharmacology
Gene Expression Regulation, Developmental
Histones / genetics
Histones / metabolism
Larva
Methylation
Mutation
Oxidoreductases, N-Demethylating / genetics
Oxidoreductases, N-Demethylating / metabolism*
Promoter Regions, Genetic
Receptors, Steroid / genetics
Receptors, Steroid / metabolism
Salivary Glands / cytology*
Salivary Glands / physiology
Transcription Factors / genetics
Transcription Factors / metabolism

Substances

DNA-Binding Proteins
Drosophila Proteins
Eip93F protein, Drosophila
Histones
Receptors, Steroid
Transcription Factors
USP protein, Drosophila
ecdysone receptor
Ecdysone
Oxidoreductases, N-Demethylating
UTX protein, Drosophila
Caspases

Grants and funding

R01 GM068016/GM/NIGMS NIH HHS/United States