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Topologically Associating Domains and Their Long-Range Contacts Are Established During Early G1 Coincident with the Establishment of the Replication-Timing Program

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Topologically Associating Domains and Their Long-Range Contacts Are Established During Early G1 Coincident with the Establishment of the Replication-Timing Program Downloaded from genome.cshlp.org on September 26, 2021 - Published by Cold Spring Harbor Laboratory Press Research Topologically associating domains and their long-range contacts are established during early G1 coincident with the establishment of the replication-timing program Vishnu Dileep,1 Ferhat Ay,2,4 Jiao Sima,1,4 Daniel L. Vera,3 William S. Noble,2 and David M. Gilbert1,3 1Department of Biological Science, Florida State University, Tallahassee, Florida 32306, USA; 2Department of Genome Sciences, University of Washington, Seattle, Washington 98195, USA; 3Center for Genomics and Personalized Medicine, Florida State University, Tallahassee, Florida 32306, USA Mammalian genomes are partitioned into domains that replicate in a defined temporal order. These domains can replicate at similar times in all cell types (constitutive) or at cell type-specific times (developmental). Genome-wide chromatin confor- mation capture (Hi-C) has revealed sub-megabase topologically associating domains (TADs), which are the structural coun- terparts of replication domains. Hi-C also segregates inter-TAD contacts into defined 3D spatial compartments that align precisely to genome-wide replication timing profiles. Determinants of the replication-timing program are re-established dur- ing early G1 phase of each cell cycle and lost in G2 phase, but it is not known when TAD structure and inter-TAD contacts are re-established after their elimination during mitosis. Here, we use multiplexed 4C-seq to study dynamic changes in chro- matin organization during early G1. We find that both establishment of TADs and their compartmentalization occur during early G1, within the same time frame as establishment of the replication-timing program. Once established, this 3D organi- zation is preserved either after withdrawal into quiescence or for the remainder of interphase including G2 phase, implying 3D structure is not sufficient to maintain replication timing. Finally, we find that developmental domains are less well com- partmentalized than constitutive domains and display chromatin properties that distinguish them from early and late con- stitutive domains. Overall, this study uncovers a strong connection between chromatin re-organization during G1, establishment of replication timing, and its developmental control. [Supplemental material is available for this article.] Mammalian cells replicate their genomes in a defined temporal or- point (TDP). The TDP is coincident with the cytogenetically ob- der (“replication-timing program”) that is cell type-specific and al- served 3D repositioning and anchorage of chromatin domains to tered in many diseases (Rhind and Gilbert 2013). Almost half of their final interphase positions in the newly formed nucleus the genome changes replication timing during development in (Dimitrova and Gilbert 1999; Walter et al. 2003; Thomson et al. units of 400–800 kb, designated replication domains (RDs) (Ryba 2004). The 3D organization of interphase chromatin in mammals et al. 2010). As a result, RDs can be categorized as replicating either has been linked to several genome-wide processes such as DNA at the same time in all cell types (constitutive RDs) or at different replication, long-range gene regulation, and chromosomal translo- times in different cell types (developmental RDs) (Hiratani et al. cations (Ryba et al. 2010; Moindrot et al. 2012; Zhang et al. 2012; 2008). The boundaries of both constitutive and developmental Denholtz et al. 2013; Ay et al. 2014; Sima and Gilbert 2014). RDs are stable across cell types, but the subnuclear position, chro- Applications of genome-wide chromatin conformation capture matin structure, and transcriptional state change coordinately (Hi-C) have revealed organization of chromatin into sub-megabase with replication timing changes for developmental RDs. In general, topologically associating domains (TADs) that are preserved across early replication is correlated with transcriptional activity (Hatton cell types and compartmentalization of chromatin contacts be- et al. 1988; Hiratani et al. 2010; Ryba et al. 2010). Although RDs tween TADs (inter-TAD interactions) into larger scale folding states are regulated independently, tandem RDs often replicate at similar that are cell type-specific (Lieberman-Aiden et al. 2009; Dixon times, resulting in larger regions of similar replication timing that et al. 2012; Nora et al. 2012). Strong correlations between replica- can fractionate or consolidate during differentiation depending tion timing and chromatin contacts in the interphase nucleus on the distribution of constitutive and developmental domains have revealed two important structure-function relationships. (Hiratani et al. 2008). First, boundaries of TADs align to the boundaries of RDs, demon- The replication-timing program is re-established in each cell strating that TADs are the units of replication timing control cycle at a point during early G1 phase termed the timing decision © 2015 Dileep et al. This article is distributed exclusively by Cold Spring Harbor Laboratory Press for the first six months after the full-issue publication 4These authors contributed equally to this work. date (see http://genome.cshlp.org/site/misc/terms.xhtml). After six months, it Corresponding author: [email protected] is available under a Creative Commons License (Attribution-NonCommercial Article published online before print. Article, supplemental material, and publi- 4.0 International), as described at http://creativecommons.org/licenses/by- cation date are at http://www.genome.org/cgi/doi/10.1101/gr.183699.114. nc/4.0/. 1104 Genome Research 25:1104–1113 Published by Cold Spring Harbor Laboratory Press; ISSN 1088-9051/15; www.genome.org www.genome.org Downloaded from genome.cshlp.org on September 26, 2021 - Published by Cold Spring Harbor Laboratory Press Chromatin folding and cell cycle (Pope et al. 2014). Second, inter-TAD interactions segregate the ge- eral G1-phase time points (Fig. 1B). The results revealed that the nome into spatial compartments that precisely reflect the replica- interphase organization of the chosen RDs is established coinci- tion-timing program (Ryba et al. 2010; Yaffe et al. 2010). This dent with the TDP (Fig. 2). Four lines of evidence support this fold- interphase organization of chromatin contacts is dismantled dur- ing behavior of the representative regions, independent of their ing mitosis (Naumova et al. 2013), suggesting the hypothesis replication timing. First, the temporal progression of spatial com- that TADs and inter-TAD contacts are re-established after each mi- partmentalization for domains harboring each bait was visually tosis at the TDP. Here, we test this hypothesis using 4C-seq (4C) to obvious without any computational analysis as an increase in examine the re-establishment of interphase chromatin organiza- the contact frequency with regions of similar replication timing tion and its relation to replication timing in a mouse mammary ep- as the bait. Compartmentalization of both early and late RDs ithelial cell line (C127) in which the cell cycle regulation of was detectable as early as 1 h and reached completion by 3 h after replication timing has been extensively studied (Wu et al. 2006; mitosis (Fig. 2A; Supplemental Fig. 6A). This folding behavior is Lu and Gilbert 2007; Lu et al. 2010; Splinter et al. 2012). further revealed by quantification of spatial compartmentaliza- tion, determined by plotting the replication timing of the stron- Results gest contacts (top 5% highest z-scores) at each time point after mitosis (Fig. 2B; Supplemental Fig. 6B). Alternatively, applying Nuclear compartments are established during early G1 a more rigorous test for quantifying significant contacts (Methods), which also corrects for multiple testing, revealed that Employing replication timing profiles from 28 different mouse significant contacts did not appear until the TDP (Supplemental cell lines (replicationdomain.org), we identified 4C viewpoints Fig. 7A). As expected, inter-chromosomal contacts were rare and (“baits”) across three mouse chromosomes (Chr 8, Chr 16, Chr difficult to quantify. However, for those baits that had sufficient 17) whose replication times are either constitutively early, consti- inter-chromosomal contact signal strength, significant contacts tutively late, or developmentally regulated (Supplemental Table 1; (Methods) also became compartmentalized after the TDP (Supple- Supplemental Fig. 1). Cells were synchronized by mitotic shake-off mental Fig. 7B). Second, the decay in contact frequency with in- after a brief nocodazole treatment and released into G1 phase for creasing genomic distance from the bait for each time point 0.5, 1, 1.5, 2, 3, and 4 h (Methods). Using this protocol, cells are showed significant differences between pre- and post-TDP profiles synchronized precisely and homogeneously in metaphase and re- (Fig. 2C), reminiscent of Hi-C data collected during mitosis vs. in- tain features of mitotic cells that are lost upon longer nocodazole terphase (Naumova et al. 2013). The differences in decay of contact blocks, including retention of Cyclin A and activation of APC frequency showed a transition from a mitosis-like organization ubiquitin ligase activity within minutes of release (Wu et al. observed at 30 min and 1h to an interphase-like configuration 1997; Okuno et al. 2001). Within 1 h of release, the mitotic index observed by 3 and 4 h (Fig. 2C). Third, we measured the 3D dis- dropped from 98% to 2%, demonstrating rapid and efficient
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