Private Model Compression via Knowledge Distillation

The soaring demand for intelligent mobile applications calls for deploying powerful deep neural networks (DNNs) on mobile devices. However, the outstanding performance of DNNs notoriously relies on increasingly complex models, which in turn is associated with an increase in computational expense far surpassing mobile devices' capacity. What is worse, app service providers need to collect and utilize a large volume of users' data, which contain sensitive information, to build the sophisticated DNN models. Directly deploying these models on public mobile devices presents prohibitive privacy risk. To benefit from the on-device deep learning without the capacity and privacy concerns, we design a private model compression framework RONA. Following the knowledge distillation paradigm, we jointly use hint learning, distillation learning, and self learning to train a compact and fast neural network. The knowledge distilled from the cumbersome model is adaptively bounded and carefully perturbed to enforce differential privacy. We further propose an elegant query sample selection method to reduce the number of queries and control the privacy loss. A series of empirical evaluations as well as the implementation on an Android mobile device show that RONA can not only compress cumbersome models efficiently but also provide a strong privacy guarantee. For example, on SVHN, when a meaningful $(9.83,10^{-6})$-differential privacy is guaranteed, the compact model trained by RONA can obtain 20$\times$ compression ratio and 19$\times$ speed-up with merely 0.97% accuracy loss.Comment: Conference version accepted by AAAI'1

12-h clock regulation of genetic information flow by XBP1s

© The Author(s), 2020. This article is distributed under the terms of the Creative Commons Attribution License. The definitive version was published in Pan, Y., Ballance, H., Meng, H., Gonzalez, N., Kim, S., Abdurehman, L., York, B., Chen, X., Schnytzer, Y., Levy, O., Dacso, C. C., McClung, C. A., O'Malley, B. W., Liu, S., & Zhu, B. 12-h clock regulation of genetic information flow by XBP1s. Plos Biology, 18(1), (2020): e3000580, doi:10.1371/journal.pbio.3000580.Our group recently characterized a cell-autonomous mammalian 12-h clock independent from the circadian clock, but its function and mechanism of regulation remain poorly understood. Here, we show that in mouse liver, transcriptional regulation significantly contributes to the establishment of 12-h rhythms of mRNA expression in a manner dependent on Spliced Form of X-box Binding Protein 1 (XBP1s). Mechanistically, the motif stringency of XBP1s promoter binding sites dictates XBP1s’s ability to drive 12-h rhythms of nascent mRNA transcription at dawn and dusk, which are enriched for basal transcription regulation, mRNA processing and export, ribosome biogenesis, translation initiation, and protein processing/sorting in the Endoplasmic Reticulum (ER)-Golgi in a temporal order consistent with the progressive molecular processing sequence described by the central dogma information flow (CEDIF). We further identified GA-binding proteins (GABPs) as putative novel transcriptional regulators driving 12-h rhythms of gene expression with more diverse phases. These 12-h rhythms of gene expression are cell autonomous and evolutionarily conserved in marine animals possessing a circatidal clock. Our results demonstrate an evolutionarily conserved, intricate network of transcriptional control of the mammalian 12-h clock that mediates diverse biological pathways. We speculate that the 12-h clock is coopted to accommodate elevated gene expression and processing in mammals at the two rush hours, with the particular genes processed at each rush hour regulated by the circadian and/or tissue-specific pathways.This study was supported by the American Diabetes Association junior faculty development award 1-18-JDF-025 to B.Z., by funding from National Institute of Health HD07879 and 1P01DK113954 to B.W.O, by funding from National Science Foundation award 1703170 to C.C.D. and B.Z., and by funding from Brockman Foundation to C.C.D and B.W.O. This work was further supported by the UPMC Genome Center with funding from UPMC’s Immunotherapy and Transplant Center. This research was supported in part by the University of Pittsburgh Center for Research Computing through the resources provided. Research reported in this publication was further supported by the National Institute of Diabetes And Digestive And Kidney Diseases of the National Institutes of Health under award number P30DK120531 to Pittsburgh Liver Research Center, in which both S.L. and B.Z. are members. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript

Regulatory mechanisms mediated by peroxisome proliferator-activated receptor-β/δ (PPARβ/δ) in skin cancer

Considerable progress has been made during the past twenty years towards elucidating the role of peroxisome proliferator-activated receptor-β/δ (PPARβ/δ) in skin cancer. In 1999, the original notion that PPARβ/δ was involved with epithelial cell function was postulated based on a correlation between PPARβ/δ expression and the induction of mRNAs encoding proteins that mediate terminal differentiation in keratinocytes. Subsequent studies definitively revealed that PPARβ/δ could induce terminal differentiation and inhibit proliferation of keratinocytes. Molecular mechanisms have since been discovered to explain how this nuclear receptor can be targeted for preventing and treating skin cancer. This includes the regulation of terminal differentiation, mitotic signaling, endoplasmic reticulum stress, and cellular senescence. Interestingly, the effects of activating PPARβ/δ can preferentially target keratinocytes with genetic mutations associated with skin cancer. This review provides the history and current understanding of how PPARβ/δ can be targeted for both non-melanoma skin cancer and melanoma, and postulates how future approaches that modulate PPARβ/δ signaling may be developed for the prevention and treatment of these diseases

Epigenetically active chromatin in neonatal iWAT reveals GABPα as a potential regulator of beige adipogenesis

BackgroundThermogenic beige adipocytes, which dissipate energy as heat, are found in neonates and adults. Recent studies show that neonatal beige adipocytes are highly plastic and contribute to >50% of beige adipocytes in adults. Neonatal beige adipocytes are distinct from recruited beige adipocytes in that they develop independently of temperature and sympathetic innervation through poorly defined mechanisms.MethodsWe characterized the neonatal beige adipocytes in the inguinal white adipose tissue (iWAT) of C57BL6 postnatal day 3 and 20 mice (P3 and P20) by imaging, genome-wide RNA-seq analysis, ChIP-seq analysis, qRT-PCR validation, and biochemical assays.ResultsWe found an increase in acetylated histone 3 lysine 27 (H3K27ac) on the promoter and enhancer regions of beige-specific gene UCP1 in iWAT of P20 mice. Furthermore, H3K27ac ChIP-seq analysis in the iWAT of P3 and P20 mice revealed strong H3K27ac signals at beige adipocyte-associated genes in the iWAT of P20 mice. The integration of H3K27ac ChIP-seq and RNA-seq analysis in the iWAT of P20 mice reveal epigenetically active signatures of beige adipocytes, including oxidative phosphorylation and mitochondrial metabolism. We identify the enrichment of GA-binding protein alpha (GABPα) binding regions in the epigenetically active chromatin regions of the P20 iWAT, particularly on beige genes, and demonstrate that GABPα is required for beige adipocyte differentiation. Moreover, transcriptomic analysis and glucose oxidation assays revealed increased glycolytic activity in the neonatal iWAT from P20.ConclusionsOur findings demonstrate that epigenetic mechanisms regulate the development of peri-weaning beige adipocytes via GABPα. Further studies to better understand the upstream mechanisms that regulate epigenetic activation of GABPα and characterization of the metabolic identity of neonatal beige adipocytes will help us harness their therapeutic potential in metabolic diseases

Analysis of the peroxisome proliferator-activated receptor-β/δ (PPARβ/δ) cistrome reveals novel co-regulatory role of ATF4

Abstract Background The present study coupled expression profiling with chromatin immunoprecipitation sequencing (ChIP-seq) to examine peroxisome proliferator-activated receptor-β/δ (PPARβ/δ)-dependent regulation of gene expression in mouse keratinocytes, a cell type that expresses PPARβ/δ in high concentration. Results Microarray analysis elucidated eight different types of regulation that modulated PPARβ/δ-dependent gene expression of 612 genes ranging from repression or activation without an exogenous ligand, repression or activation with an exogenous ligand, or a combination of these effects. Bioinformatic analysis of ChIP-seq data demonstrated promoter occupancy of PPARβ/δ for some of these genes, and also identified the presence of other transcription factor binding sites in close proximity to PPARβ/δ bound to chromatin. For some types of regulation, ATF4 is required for ligand-dependent induction of PPARβ/δ target genes. Conclusions PPARβ/δ regulates constitutive expression of genes in keratinocytes, thus suggesting the presence of one or more endogenous ligands. The diversity in the types of gene regulation carried out by PPARβ/δ is consistent with dynamic binding and interactions with chromatin and indicates the presence of complex regulatory networks in cells expressing high levels of this nuclear receptor such as keratinocytes. Results from these studies are the first to demonstrate that differences in DNA binding of other transcription factors can directly influence the transcriptional activity of PPARβ/δ.http://deepblue.lib.umich.edu/bitstream/2027.42/112940/1/12864_2012_Article_4648.pd

Defining the Mammalian Coactivation of Hepatic 12-H Clock and Lipid Metabolism

The 12-h clock coordinates lipid homeostasis, energy metabolism, and stress rhythms via the transcriptional regulator XBP1. However, the biochemical and physiological bases for integrated control of the 12-h clock and diverse metabolic pathways remain unclear. Here, we show that steroid receptor coactivator SRC-3 coactivates XBP1 transcription and regulates hepatic 12-h cistrome and gene rhythmicity. Mice lacking SRC-3 show abnormal 12-h rhythms in hepatic transcription, metabolic functions, systemic energetics, and rate-limiting lipid metabolic processes, including triglyceride, phospholipid, and cardiolipin pathways. Notably, 12-h clock coactivation is not only preserved, with its cistromic activation priming ahead of the zeitgeber cue of light, but concomitant with rhythmic remodeling in the absence of food. These findings reveal that SRC-3 integrates the mammalian 12-h clock, energy metabolism, and membrane and lipid homeostasis and demonstrates a role for the 12-h clock machinery as an active transcriptional mechanism in anticipating physiological and metabolic energy needs and stresses

Acetylation of Histone H3K27 Signals the Transcriptional Elongation for Estrogen Receptor Alpha

As approximately 70% of human breast tumors are estrogen receptor α (ERα)-positive, estrogen and ERα play essential roles in breast cancer development. By interrupting the ERα signaling pathway, endocrine therapy has been proven to be an effective therapeutic strategy. In this study, we identified a mechanism by which Transcription Start Site (TSS)-associated histone H3K27 acetylation signals the Super Elongation Complex (SEC) to regulate transcriptional elongation of the ESR1 (ERα) gene. SEC interacts with H3K27ac on ESR1 TSS through its scaffold protein AFF4. Depletion of AFF4 by siRNA or CRISPR/Cas9 dramatically reduces expression of ESR1 and its target genes, consequently inhibiting breast cancer cell growth. More importantly, a AFF4 mutant which lacks H3K27ac interaction failed to rescue ESR1 gene expression, suggesting H3K27 acetylation at TSS region is a key mark bridging the transition from transcriptional initiation to elongation, and perturbing SEC function can be an alternative strategy for targeting ERα signaling pathway at chromatin level

TRAF4-Mediated Nonproteolytic Ubiquitination of Androgen Receptor Promotes Castration-Resistant Prostate Cancer

Castration-resistant prostate cancer (CRPC) poses a major clinical challenge with the androgen receptor (AR) remaining to be a critical oncogenic player. Several lines of evidence indicate that AR induces a distinct transcriptional program after androgen deprivation in CRPCs. However, the mechanism triggering AR binding to a distinct set of genomic loci in CRPC and how it promotes CRPC development remain unclear. We demonstrate here that atypical ubiquitination of AR mediated by an E3 ubiquitin ligase TRAF4 plays an important role in this process. TRAF4 is highly expressed in CRPCs and promotes CRPC development. It mediates K27-linked ubiquitination at the C-terminal tail of AR and increases its association with the pioneer factor FOXA1. Consequently, AR binds to a distinct set of genomic loci enriched with FOXA1- and HOXB13-binding motifs to drive different transcriptional programs including an olfactory transduction pathway. Through the surprising upregulation of olfactory receptor gene transcription, TRAF4 increases intracellular cAMP levels and boosts E2F transcription factor activity to promote cell proliferation under androgen deprivation conditions. Altogether, these findings reveal a posttranslational mechanism driving AR-regulated transcriptional reprogramming to provide survival advantages for prostate cancer cells under castration conditions