@article {68011, title = {BRD2 compartmentalizes the accessible genome.}, journal = {Nature Genetics}, volume = {54}, year = {2022}, month = {2022 Apr 11}, pages = {481-491}, abstract = {

Mammalian chromosomes are organized into megabase-sized compartments that are further subdivided into topologically associating domains (TADs). While the formation of TADs is dependent on cohesin, the mechanism behind compartmentalization remains enigmatic. Here, we show that the bromodomain and extraterminal (BET) family scaffold protein BRD2 promotes spatial mixing and compartmentalization of active chromatin after cohesin loss. This activity is independent of transcription but requires BRD2 to recognize acetylated targets through its double bromodomain and interact with binding partners with its low-complexity domain. Notably, genome compartmentalization mediated by BRD2 is antagonized on the one hand by cohesin and on the other hand by the BET homolog protein BRD4, both of which inhibit BRD2 binding to chromatin. Polymer simulation of our data supports a BRD2-cohesin interplay model of nuclear topology, in which genome compartmentalization results from a competition between loop extrusion and chromatin-state-specific affinity interactions.

}, keywords = {Animals, Cell Cycle Proteins, Chromatin, Chromosomes, Mammals, Nuclear Proteins, Protein Binding, Protein Domains, Transcription Factors}, issn = {1546-1718}, doi = {10.1038/s41588-022-01044-9}, author = {Xie, Liangqi and Dong, Peng and Qi, Yifeng and Hsieh, Tsung-Han S and English, Brian P and Jung, Seolkyoung and Chen, Xingqi and De Marzio, Margherita and Casellas, Rafael and Chang, Howard Y and Zhang, Bin and Tjian, Robert and Liu, Zhe} } @article {48731, title = {Myc Regulates Chromatin Decompaction and Nuclear Architecture during B Cell Activation.}, journal = {Molecular Cell}, volume = {67}, year = {2017}, month = {2017 Jul 28}, pages = {566-78}, abstract = {

50 years ago, Vincent Allfrey and colleagues discovered that lymphocyte activation triggers massive acetylation of chromatin. However, the molecular mechanisms driving epigenetic accessibility are still unknown. We here show that stimulated lymphocytes decondense chromatin by three differentially regulated steps. First, chromatin is repositioned away from the nuclear periphery in response to global acetylation. Second, histone nanodomain clusters decompact into mononucleosome fibers through a mechanism that requires Myc and continual energy input. Single-molecule imaging shows that this step lowers transcription factor residence time and non-specific collisions during sampling for DNA targets. Third, chromatin interactions shift from long range to predominantly short range, and CTCF-mediated loops and contact domains double in numbers. This architectural change facilitates cognate promoter-enhancer contacts and also requires Myc and continual ATP production. Our results thus define the nature and transcriptional impact of chromatin decondensation and reveal an unexpected role for Myc in the establishment of nuclear topology in mammalian cells.

}, issn = {1097-4164}, doi = {10.1016/j.molcel.2017.07.013}, author = {Kieffer-Kwon, Kyong-Rim and Nimura, Keisuke and Rao, Suhas S P and Xu, Jianliang and Jung, Seolkyoung and Pekowska, Aleksandra and Dose, Marei and Stevens, Evan and Mathe, Ewy and Dong, Peng and Huang, Su-Chen and Ricci, Maria Aurelia and Baranello, Laura and Zheng, Ying and Ardori, Francesco Tomassoni and Resch, Wolfgang and Stavreva, Diana and Nelson, Steevenson and McAndrew, Michael and Casellas, Adriel and Finn, Elizabeth and Gregory, Charles and St Hilaire, Brian Glenn and Johnson, Steven M and Dubois, Wendy and Cosma, Maria Pia and Batchelor, Eric and Levens, David and Phair, Robert D and Misteli, Tom and Tessarollo, Lino and Hager, Gordon and Lakadamyali, Melike and Liu, Zhe and Floer, Monique and Shroff, Hari and Aiden, Erez Lieberman and Casellas, Rafael} } @article {47035, title = {Combinatorial DNA rearrangement facilitates the origin of new genes in ciliates.}, journal = {Genome Biology and Evolution}, volume = {7}, year = {2015}, month = {2015 Sep 2}, pages = {2859-70}, abstract = {

Programmed genome rearrangements in the unicellular eukaryote Oxytricha trifallax produce a transcriptionally active somatic nucleus from a copy of its germline nucleus during development. This process eliminates noncoding sequences that interrupt coding regions in the germline genome, and joins over 225,000 remaining DNA segments, some of which require inversion or complex permutation to build functional genes. This dynamic genomic organization permits some single DNA segments in the germline to contribute to multiple, distinct somatic genes via alternative processing. Like alternative mRNA splicing, the combinatorial assembly of DNA segments contributes to genetic variation and facilitates the evolution of new genes. In this study, we use comparative genomic analysis to demonstrate that the emergence of alternative DNA splicing is associated with the origin of new genes. Short duplications give rise to alternative gene segments that are spliced to the shared gene segments. Alternative gene segments evolve faster than shared, constitutive segments. Genes with shared segments frequently have different expression profiles, permitting functional divergence. This study reports alternative DNA splicing as a mechanism of new gene origination, illustrating how the process of programmed genome rearrangement gives rise to evolutionary innovation.

}, issn = {1759-6653}, doi = {10.1093/gbe/evv172}, author = {Chen, Xiao and Jung, Seolkyoung and Beh, Leslie Y and Eddy, Sean R and Landweber, Laura F} } @article {6526, title = {The Oxytricha trifallax macronuclear genome: a complex eukaryotic genome with 16,000 tiny chromosomes.}, journal = {PLoS Biology}, volume = {11}, year = {2013}, month = {2013 Jan}, pages = {e1001473}, abstract = {

The macronuclear genome of the ciliate Oxytricha trifallax displays an extreme and unique eukaryotic genome architecture with extensive genomic variation. During sexual genome development, the expressed, somatic macronuclear genome is whittled down to the genic portion of a small fraction (\~{}5\%) of its precursor "silent" germline micronuclear genome by a process of "unscrambling" and fragmentation. The tiny macronuclear "nanochromosomes" typically encode single, protein-coding genes (a small portion, 10\%, encode 2-8 genes), have minimal noncoding regions, and are differentially amplified to an average of \~{}2,000 copies. We report the high-quality genome assembly of \~{}16,000 complete nanochromosomes (\~{}50 Mb haploid genome size) that vary from 469 bp to 66 kb long (mean \~{}3.2 kb) and encode \~{}18,500 genes. Alternative DNA fragmentation processes \~{}10\% of the nanochromosomes into multiple isoforms that usually encode complete genes. Nucleotide diversity in the macronucleus is very high (SNP heterozygosity is \~{}4.0\%), suggesting that Oxytricha trifallax may have one of the largest known effective population sizes of eukaryotes. Comparison to other ciliates with nonscrambled genomes and long macronuclear chromosomes (on the order of 100 kb) suggests several candidate proteins that could be involved in genome rearrangement, including domesticated MULE and IS1595-like DDE transposases. The assembly of the highly fragmented Oxytricha macronuclear genome is the first completed genome with such an unusual architecture. This genome sequence provides tantalizing glimpses into novel molecular biology and evolution. For example, Oxytricha maintains tens of millions of telomeres per cell and has also evolved an intriguing expansion of telomere end-binding proteins. In conjunction with the micronuclear genome in progress, the O. trifallax macronuclear genome will provide an invaluable resource for investigating programmed genome rearrangements, complementing studies of rearrangements arising during evolution and disease.

}, keywords = {Base Sequence, DNA, DNA Copy Number Variations, DNA Fragmentation, Gene Amplification, Gene Rearrangement, Genes, Genetic Variation, Genome, Macronucleus, Messenger, Molecular Sequence Data, Oxytricha, Protein Binding, Protozoan, RNA, Sequence Analysis, Telomere}, issn = {1545-7885}, doi = {10.1371/journal.pbio.1001473}, author = {Swart, Estienne C and Bracht, John R and Magrini, Vincent and Minx, Patrick and Chen, Xiao and Zhou, Yi and Khurana, Jaspreet S and Goldman, Aaron D and Nowacki, Mariusz and Schotanus, Klaas and Jung, Seolkyoung and Fulton, Robert S and Ly, Amy and McGrath, Sean and Haub, Kevin and Wiggins, Jessica L and Storton, Donna and Matese, John C and Parsons, Lance and Chang, Wei-Jen and Bowen, Michael S and Stover, Nicholas A and Jones, Thomas A and Eddy, Sean R. and Herrick, Glenn A and Doak, Thomas G and Wilson, Richard K and Mardis, Elaine R and Landweber, Laura F} } @article {6507, title = {Exploiting Oxytricha trifallax nanochromosomes to screen for non-coding RNA genes.}, journal = {Nucleic Acids Research}, volume = {39}, year = {2011}, month = {2011 Sep 1}, pages = {7529-47}, abstract = {

We took advantage of the unusual genomic organization of the ciliate Oxytricha trifallax to screen for eukaryotic non-coding RNA (ncRNA) genes. Ciliates have two types of nuclei: a germ line micronucleus that is usually transcriptionally inactive, and a somatic macronucleus that contains a reduced, fragmented and rearranged genome that expresses all genes required for growth and asexual reproduction. In some ciliates including Oxytricha, the macronuclear genome is particularly extreme, consisting of thousands of tiny {\textquoteright}nanochromosomes{\textquoteright}, each of which usually contains only a single gene. Because the organism itself identifies and isolates most of its genes on single-gene nanochromosomes, nanochromosome structure could facilitate the discovery of unusual genes or gene classes, such as ncRNA genes. Using a draft Oxytricha genome assembly and a custom-written protein-coding genefinding program, we identified a subset of nanochromosomes that lack any detectable protein-coding gene, thereby strongly enriching for nanochromosomes that carry ncRNA genes. We found only a small proportion of non-coding nanochromosomes, suggesting that Oxytricha has few independent ncRNA genes besides homologs of already known RNAs. Other than new members of known ncRNA classes including C/D and H/ACA snoRNAs, our screen identified one new family of small RNA genes, named the Arisong RNAs, which share some of the features of small nuclear RNAs.

}, keywords = {Base Sequence, Chromosomes, Conserved Sequence, Genes, Genome, Genomics, Introns, Oxytricha, Protozoan, RNA, Small Nuclear, Small Nucleolar, Untranslated}, issn = {1362-4962}, doi = {10.1093/nar/gkr501}, author = {Jung, Seolkyoung and Swart, Estienne C and Minx, Patrick J and Magrini, Vincent and Mardis, Elaine R and Landweber, Laura F and Eddy, Sean R.} }