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Tissue-Specific BMAL1 Cistromes Reveal That Rhythmic Transcription Is Associated with Rhythmic Enhancer–Enhancer Interactions

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Tissue-Specific BMAL1 Cistromes Reveal That Rhythmic Transcription Is Associated with Rhythmic Enhancer–Enhancer Interactions Downloaded from genesdev.cshlp.org on October 7, 2021 - Published by Cold Spring Harbor Laboratory Press Tissue-specific BMAL1 cistromes reveal that rhythmic transcription is associated with rhythmic enhancer–enhancer interactions Joshua R. Beytebiere,1 Alexandra J. Trott,1,2 Ben J. Greenwell,1,2 Collin A. Osborne,1,2 Helene Vitet,1 Jessica Spence,1 Seung-Hee Yoo,3 Zheng Chen,3 Joseph S. Takahashi,4 Noushin Ghaffari,5,6 and Jerome S. Menet1,2 1Department of Biology, Center for Biological Clocks Research, Texas A&M University, College Station, Texas 77843, USA; 2Program of Genetics, Texas A&M University, College Station, Texas 77843, USA; 3Department of Biochemistry and Molecular Biology, The University of Texas Health Science Center at Houston, Houston, Texas 77030, USA; 4Department of Neuroscience, Howard Hughes Medical Institute, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA; 5Center for Bioinformatics and Genomic Systems Engineering (CBGSE), 6AgriLife Genomics and Bioinformatics, Texas A&M AgriLife Research, College Station, Texas 77845, USA The mammalian circadian clock relies on the transcription factor CLOCK:BMAL1 to coordinate the rhythmic ex- pression of thousands of genes. Consistent with the various biological functions under clock control, rhythmic gene expression is tissue-specific despite an identical clockwork mechanism in every cell. Here we show that BMAL1 DNA binding is largely tissue-specific, likely because of differences in chromatin accessibility between tissues and cobinding of tissue-specific transcription factors. Our results also indicate that BMAL1 ability to drive tissue-spe- cific rhythmic transcription is associated with not only the activity of BMAL1-bound enhancers but also the activity of neighboring enhancers. Characterization of physical interactions between BMAL1 enhancers and other cis-reg- ulatory regions by RNA polymerase II chromatin interaction analysis by paired-end tag (ChIA-PET) reveals that rhythmic BMAL1 target gene expression correlates with rhythmic chromatin interactions. These data thus support that much of BMAL1 target gene transcription depends on BMAL1 capacity to rhythmically regulate a network of enhancers. [Keywords: circadian clock; enhancer–enhancer interactions; tissue-specific cistromes; transcription] Supplemental material is available for this article. Received November 2, 2018; revised version accepted January 2, 2019. Circadian clocks are found ubiquitously across all king- transcription more potently during the middle of the day, doms of life and provide a time-keeping mechanism for or- and maximal repression occurs during the middle of the ganisms to anticipate rhythmic environmental changes. night (Rey et al. 2011; Koike et al. 2012). CLOCK: In mammals, virtually every cell harbors the same circadi- BMAL1 is also responsible for the transcriptional regula- an clockwork that regulates rhythmic gene expression tion of many clock-controlled genes, which allows for along with temporal cues and systemic signals, such that rhythms in biochemistry, physiology, and behavior (Panda biological functions occur at the most appropriate time 2016). of day. The mammalian circadian clock relies on transcrip- Characterization of the rhythmic transcriptional out- tional feedback loops initiated by the heterodimeric tran- puts driven by the circadian clock indicates that genes ex- scription factor CLOCK:BMAL1 (Partch et al. 2014; pressed in a rhythmic manner vary greatly between tissues Takahashi 2017). CLOCK:BMAL1 rhythmically binds in the mouse (Panda et al. 2002; Storch et al. 2002; Zhang DNA to drive the rhythmic transcription of the genes Pe- et al. 2014). Similar findings in plants, insects, and pri- riod (Per1, Per2, and Per3) and Cryptochrome (Cry1 and mates also revealed that circadian gene expression is large- Cry2), which, upon translation, form a repressive complex ly tissue-specific (Endo et al. 2014; Meireles-Filho et al. that feedbacks to inhibit CLOCK:BMAL1-mediated tran- scription. CLOCK:BMAL1 binds to E-boxes and activates © 2019 Beytebiere et al. This article is distributed exclusively by Cold Spring Harbor Laboratory Press for the first six months after the full-issue publication date (see http://genesdev.cshlp.org/site/misc/terms.xhtml). Corresponding author: [email protected] After six months, it is available under a Creative Commons License (Attri- Article published online ahead of print. Article and publication date are bution-NonCommercial 4.0 International), as described at http://creative- online at http://www.genesdev.org/cgi/doi/10.1101/gad.322198.118. commons.org/licenses/by-nc/4.0/. 294 GENES & DEVELOPMENT 33:294–309 Published by Cold Spring Harbor Laboratory Press; ISSN 0890-9369/19; www.genesdev.org Downloaded from genesdev.cshlp.org on October 7, 2021 - Published by Cold Spring Harbor Laboratory Press Regulation of rhythmic transcription by BMAL1 2014; Mure et al. 2018). However, it is still unknown how with peaks common to more than one tissue (Fig. 1C; see the same circadian clock mechanism can generate tissue- below). specific rhythmic gene expression. Previous work in Dro- To ensure that differences in BMAL1 ChIP-seq signal sophila revealed that CLOCK:CYC, the CLOCK:BMAL1 between tissues represent true biological variation, we homolog, exhibits tissue-specific DNA binding between compared BMAL1 ChIP-seq signal between each of the the body and head, and that much of this tissue specificity nine data sets and found a high degree of correlation be- is due to the cooperation between CLOCK:CYC and tis- tween samples originating from the same tissue but not sue-specific transcription factors (ts-TFs) (Meireles-Filho between tissues (Fig. 1D). Interreplicates variation be- et al. 2014). Tissue-specific binding of another mammalian tween replicates was higher for the kidney than for the liv- clock component, Rev-erbα, has also been described, but er and heart; however, this might reflect the higher cell the underlying mechanisms have not yet been character- type heterogeneity and the variability in the chromatin ized (Zhang et al. 2015). accessibility landscape that are observed in the kidney To address the mechanisms by which the mammalian when compared with the heart and liver (Cusanovich circadian clock generates tissue-specific circadian tran- et al. 2018). We also found that BMAL1 ChIP-seq signal scriptional programs, we performed BMAL1 chromatin at core clock genes is nearly identical between all three immunoprecipitation (ChIP) at the genome-wide level tissues, further indicating that differences in BMAL1- (ChIP-seq) in the mouse liver, kidney, and heart. Our binding signal between tissues stem from biological vari- data revealed that the majority of BMAL1 DNA binding ations (Fig. 1E). Consistent with this finding, gene ontolo- is tissue-specific and suggest that accessibility of the chro- gy analysis of BMAL1 target genes for each tissue revealed matin (as defined by DNase I-hypersensitive sites [DHSs]) that while circadian rhythm and other general terms are (Thurman et al. 2012) and that cobinding of ts-TFs ac- enriched in all three tissues, tissue-specific biological pro- counts for much of this tissue specificity. In addition, we cesses are enriched in a tissue-specific manner (Fig. 1F). found large discrepancies between BMAL1 DNA binding Many of these tissue-specific processes have been shown and rhythmic gene expression with, for example, many to be regulated by the circadian clock, such as glycogen genes targeted by BMAL1 in all three tissues only exhibit- synthesis, lipid metabolism, and cholesterol homeostasis ing rhythmicity in a single tissue. Characterization of the in the liver (Doi et al. 2010; Gnocchi et al. 2015; Ma et al. underlying mechanism suggests that the ability of BMAL1 2015) and blood pressure and vascular smooth muscle to drive tissue-specific rhythmic gene expression depends contraction in the heart (Wang et al. 2008; Xie et al. on how BMAL1 promotes not only the activity of the DHSs 2015). Together, these results indicate that BMAL1 pre- to which it binds but also the activity of other neighboring dominantly binds DNA in a tissue-specific manner and DHSs. Together, our data suggest that BMAL1 transcrip- targets genes involved in the regulation of tissue-specific tional output is controlled through enhancer–enhancer in- biological functions. teractions and that BMAL1-driven rhythmic transcription depends on the capacity of BMAL1 to rhythmically regu- Chromatin accessibility contributes to tissue-specific late a network of DHSs. BMAL1 DNA binding To understand the large differences in BMAL1 ChIP-seq Results signal between tissues, we set out to define the mecha- nisms that enable BMAL1 to bind DNA in a tissue-specific BMAL1 DNA-binding signal is largely tissue-specific manner. Characterization of the chromatin landscape by To determine whether BMAL1 cistrome differs between the ENCODE consortium and others revealed that tissues, we performed BMAL1 ChIP-seq in the mouse liv- 94.4% of TF ChIP-seq peaks are located in an accessible er, kidney, and heart with three biological replicates per chromatin region; i.e., a region that is hypersensitive to tissue. Because CLOCK:BMAL1 DNA-binding sites in DNase I (Thurman et al. 2012; Yue et al. 2014). Because the liver are virtually identical over the course of the day mouse liver CLOCK:BMAL1 DNA-binding sites are lo- and only exhibit homogenous differences in DNA-binding cated predominantly in DHSs (Sobel et al. 2017; Trott strength (Rey et al. 2011; Koike et al. 2012), we performed and Menet 2018), we hypothesized that tissue-specific BMAL1 ChIP at the time of maximal binding; i.e., Zeitge- BMAL1 binding may be, at least in part, caused by differ- ber time 6 (ZT6; ZT0 is defined at the light on signal) (Sup- ences in DNA accessibility between the liver, kidney, plemental Fig. S1A). Identification of BMAL1 DNA- and heart. To test our hypothesis, we used DNase sequenc- binding sites using HOMER software (Heinz et al. 2010) re- ing (DNase-seq) data sets from the mouse ENCODE pro- vealed that most BMAL1 peaks were tissue-specific, with ject (Vierstra et al. 2014; Yue et al.
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