Nature Cell Biology: online 17 November 2014; DOI: 10.1038/ncb3062

Foxk proteins repress the initiation of starvation-induced atrophy and autophagy programs

Bowman, CJ, Ayer DE , and Dynlacht ,BD

Autophagy is the primary catabolic process triggered in response to starvation. Although autophagic regulation within the cytosolic compartment is well established, it is becoming clear that nuclear events also regulate the induction or repression of autophagy. Nevertheless, a thorough understanding of the mechanisms by which sequence-specific transcription factors modulate expression of genes required for autophagy is lacking. Here, we identify Foxk proteins (Foxk1 and Foxk2) as transcriptional repressors of autophagy in muscle cells and fibroblasts. Interestingly, Foxk1/2 serve to counter-balance another forkhead transcription factor, Foxo3, which induces an overlapping set of autophagic and atrophic targets in muscle. Foxk1/2 specifically recruits Sin3A–HDAC complexes to restrict acetylation of histone H4 and expression of critical autophagy genes. Remarkably, mTOR promotes the transcriptional activity of Foxk1 by facilitating nuclear entry to specifically limit basal levels of autophagy in nutrient-rich conditions. Our study highlights an ancient, conserved mechanism whereby nutritional status is interpreted by mTOR to restrict autophagy by repressing essential autophagy genes through Foxk–Sin3-mediated transcriptional control.

PNAS 2014 ; published ahead of print June 9, 2014, doi:10.1073/pnas.1323265111

Primary cilia control Hedgehog signaling during muscle differentiationand are deregulated in rhabdomyosarcoma

Fu W, Asp P, Canter B and Dynlacht BD

The primary cilium is an organelle emanating from the cell surface, and recent evidence suggests that it regulates various cellular signaling pathways and development and that aberrations in its assembly and function could result in tumorigenesis. Skeletal muscle differentiation proceeds through a temporally defined series of events to form multinucleated myofibers, and in rhabdomyosarcomas (RMS), myoblasts fail to differentiate. However, whether primary cilia are functionally linked to normal muscle differentiation or RMS is not known. In this study we show that in skeletal myoblasts, primary cilia are important for proliferation, hedgehog signaling, and differentiation. Furthermore, the deregulation of cilia and hedgehog in RMS could suggest the utility of therapeutically targeting ciliary components in these tumors.

Journal of Cell Biology, January 13, 2014, doi10.1083/jcb.201304153

The CP110-interacting proteins Talpid3 and Cep290 play overlapping roles in cilia assembly. 

Kobayashi T, Kim S, Lin YC, Inoue T, Dynlacht BD.

We have identified Talpid3/KIAA0586 as a component of a CP110-containing protein complex important for centrosome and cilia function. Talpid3 assembles a ring-like structure at the extreme distal end of centrioles. Ablation of Talpid3 resulted in an aberrant distribution of centriolar satellites involved in protein trafficking to centrosomes as well as cilia assembly defects, reminiscent of loss of Cep290, another CP110-associated protein. Talpid3 depletion also led to mislocalization of Rab8a, a small GTPase thought to be essential for ciliary vesicle formation. Expression of activated Rab8a suppressed cilia assembly defects provoked by Talpid3 depletion, suggesting that Talpid3 affects cilia formation through Rab8a recruitment and/or activation. Remarkably, ultrastructural analyses showed that Talpid3 is required for centriolar satellite dispersal, which precedes the formation of mature ciliary vesicles, a process requiring Cep290. These studies suggest that Talpid3 and Cep290 play overlapping and distinct roles in ciliary vesicle formation through regulation of centriolar satellite accretion and Rab.

Molecular Cell, March 20, 2014, Vol 53 No. 6, pg 979-992

A Role for H3K4 Monomethylation in Gene Repression and Partitioning of Chromatin Readers

Cheng J, Blum R, Bowman, C, Hu D, Shilatifard A, Shen S, Dynlacht BD

Monomethylation of lysine 4 on histone H3 (H3K4me1) is a well-established feature of enhancers and promoters, although its function is unknown. Here, we uncover roles for H3K4me1 in diverse cell types. Remarkably, we find that MLL3/4 provokes monomethylation of promoter regions and the conditional repression of muscle and inflammatory response genes in myoblasts. During myogenesis, muscle genes are activated, lose MLL3 occupancy, and become H3K4-trimethylated through an alternative COMPASS complex. Monomethylation-mediated repression was not restricted to skeletal muscle. Together with H3K27me3 and H4K20me1, H3K4me1 was associated with transcriptional silencing in embryonic fibroblasts, macrophages, and human embryonic stem cells (ESCs). On promoters of active genes, we find that H3K4me1 spatially demarcates the recruitment of factors that interact with H3K4me3, including ING1, which, in turn, recruits Sin3A. Our findings point to a unique role for H3K4 monomethylation in establishing boundaries that restrict the recruitment of chromatin-modifying enzymes to defined regions within promoters.