Epigenetic regulation of microRNA-10b and targeting of oncogenic MAPRE1 in gastric cancer

Kim, Kwoneel,Lee, Han-Chul,Park, Jong-Lyul,Kim, Mirang,Kim, Seon-Young,Noh, Seung-Moo,Song, Kyu-Sang,Kim, Jin Cheon,Kim, Yong Sung LANDERS BIOSCIENCE 2011 Epigenetics Vol.6 No.6

Genetic Architecture of Transcription and Chromatin Regulation

Kim, Kwoneel,Bang, Hyoeun,Lee, Kibaick,Choi, Jung Kyoon Korea Genome Organization 2015 Genomics & informatics Vol.13 No.2

DNA microarray and next-generation sequencing provide data that can be used for the genetic analysis of multiple quantitative traits such as gene expression levels, transcription factor binding profiles, and epigenetic signatures. In particular, chromatin opening is tightly coupled with gene transcription. To understand how these two processes are genetically regulated and associated with each other, we examined the changes of chromatin accessibility and gene expression in response to genetic variation by means of quantitative trait loci mapping. Regulatory patterns commonly observed in yeast and human across different technical platforms and experimental designs suggest a higher genetic complexity of transcription regulation in contrast to a more robust genetic architecture of chromatin regulation.

Global transcription network incorporating distal regulator binding reveals selective cooperation of cancer drivers and risk genes

Kim, Kwoneel,Yang, Woojin,Lee, Kang Seon,Bang, Hyoeun,Jang, Kiwon,Kim, Sang Cheol,Yang, Jin Ok,Park, Seongjin,Park, Kiejung,Choi, Jung Kyoon Oxford University Press 2015 Nucleic acids research Vol.43 No.12

<P>Global network modeling of distal regulatory interactions is essential in understanding the overall architecture of gene expression programs. Here, we developed a Bayesian probabilistic model and computational method for global causal network construction with breast cancer as a model. Whereas physical regulator binding was well supported by gene expression causality in general, distal elements in intragenic regions or loci distant from the target gene exhibited particularly strong functional effects. Modeling the action of long-range enhancers was critical in recovering true biological interactions with increased coverage and specificity overall and unraveling regulatory complexity underlying tumor subclasses and drug responses in particular. Transcriptional cancer drivers and risk genes were discovered based on the network analysis of somatic and genetic cancer-related DNA variants. Notably, we observed that the risk genes were functionally downstream of the cancer drivers and were selectively susceptible to network perturbation by tumorigenic changes in their upstream drivers. Furthermore, cancer risk alleles tended to increase the susceptibility of the transcription of their associated genes. These findings suggest that transcriptional cancer drivers selectively induce a combinatorial misregulation of downstream risk genes, and that genetic risk factors, mostly residing in distal regulatory regions, increase transcriptional susceptibility to upstream cancer-driving somatic changes.</P>

Genetic Landscape of Open Chromatin in Yeast

Lee, Kibaick,Kim, Sang Cheol,Jung, Inkyung,Kim, Kwoneel,Seo, Jungmin,Lee, Heun-Sik,Bogu, Gireesh K.,Kim, Dongsup,Lee, Sanghyuk,Lee, Byungwook,Choi, Jung Kyoon Public Library of Science 2013 PLoS genetics Vol.9 No.2

<▼1><P>Chromatin regulation underlies a variety of DNA metabolism processes, including transcription, recombination, repair, and replication. To perform a quantitative genetic analysis of chromatin accessibility, we obtained open chromatin profiles across 96 genetically different yeast strains by FAIRE (formaldehyde-assisted isolation of regulatory elements) assay followed by sequencing. While 5∼10% of open chromatin region (OCRs) were significantly affected by variations in their underlying DNA sequences, subtelomeric areas as well as gene-rich and gene-poor regions displayed high levels of sequence-independent variation. We performed quantitative trait loci (QTL) mapping using the FAIRE signal for each OCR as a quantitative trait. While individual OCRs were associated with a handful of specific genetic markers, gene expression levels were associated with many regulatory loci. We found multi-target <I>trans</I>-loci responsible for a very large number of OCRs, which seemed to reflect the widespread influence of certain chromatin regulators. Such regulatory hotspots were enriched for known regulatory functions, such as recombinational DNA repair, telomere replication, and general transcription control. The OCRs associated with these multi-target <I>trans</I>-loci coincided with recombination hotspots, telomeres, and gene-rich regions according to the function of the associated regulators. Our findings provide a global quantitative picture of the genetic architecture of chromatin regulation.</P></▼1><▼2><P><B>Author Summary</B></P><P>Quantitative trait loci (QTL) mapping is a genetic approach that allows the identification of genetic factors underlying a phenotype of interest. Genomic technologies such as DNA microarray and next-generation sequencing provide data that can be used for the analysis of multiple molecular phenotypes. For example, the expression levels of thousands of genes can be associated with subject-specific genome-wide genetic information in expression QTL mapping. Similarly, the genetic regulation of transcription factor binding or epigenetic mechanisms such as DNA methylation or chromatin structure has begun to be investigated. In particular, the mechanisms controlling chromatin accessibility have attracted special interest due to their importance in a variety of DNA regulation processes including recombination, repair, replication, and transcription. In this work, we sought to dissect the genetic architecture of chromatin accessibility regulation by harnessing the power of genetic and genomic techniques. By analyzing open (accessible) chromatin maps of multiple yeast individuals in association with their genetic backgrounds, we were able to characterize the regulatory structure of chromatin traits versus that of gene expression. Importantly, we observed that the genetic loci responsible for multiple open chromatin regions were enriched for known regulatory factors.</P></▼2>

Network perturbation by recurrent regulatory variants in cancer

Jang, Kiwon,Kim, Kwoneel,Cho, Ara,Lee, Insuk,Choi, Jung Kyoon Public Library of Science 2017 PLoS computational biology Vol.13 No.3

<▼1><P>Cancer driving genes have been identified as recurrently affected by variants that alter protein-coding sequences. However, a majority of cancer variants arise in noncoding regions, and some of them are thought to play a critical role through transcriptional perturbation. Here we identified putative transcriptional driver genes based on combinatorial variant recurrence in <I>cis</I>-regulatory regions. The identified genes showed high connectivity in the cancer type-specific transcription regulatory network, with high outdegree and many downstream genes, highlighting their causative role during tumorigenesis. In the protein interactome, the identified transcriptional drivers were not as highly connected as coding driver genes but appeared to form a network module centered on the coding drivers. The coding and regulatory variants associated via these interactions between the coding and transcriptional drivers showed exclusive and complementary occurrence patterns across tumor samples. Transcriptional cancer drivers may act through an extensive perturbation of the regulatory network and by altering protein network modules through interactions with coding driver genes.</P></▼1><▼2><P><B>Author summary</B></P><P>Identifying driver variants is a current challenge facing cancer genomics. A well-established and robust method for this is to find recurrence in large cohorts of samples. Recurrence patterns of amino acid-changing variants can reveal oncogenes and tumor suppressor genes. However, such single-gene approaches have limitations because of rare variants. Therefore, recurrently affected protein complexes, network modules, or signaling pathways have been identified based on network-level recurrence. Here we dissect chromatin interactome to identify <I>cis</I>-regulatory variants that show high gene-level recurrence. We then employ the gene regulatory network and protein interactome to characterize putative cancer genes with <I>cis</I>-regulatory variant recurrence. These genes were located at critical positions in the regulatory network. By contrast, they are at the circumference in the protein interactome; instead, they form a network module with coding cancer genes located at hub positions. Furthermore, the coding and regulatory variants associated via these interactions showed exclusive and complementary occurrence patterns across tumor samples. Therefore, we suggest that transcriptional cancer drivers may act through an extensive perturbation of the regulatory network and by altering protein network modules through interactions with coding driver genes.</P></▼2>

Genome-wide reorganization of histone H2AX toward particular fragile sites on cell activation

Seo, Jungmin,Kim, Kwoneel,Chang, Dong-Yeop,Kang, Ho-Bum,Shin, Eui-Cheol,Kwon, Jongbum,Choi, Jung Kyoon Oxford University Press 2014 Nucleic acids research Vol.42 No.2

<P>γH2AX formation by phosphorylation of the histone variant H2AX is the key process in the repair of DNA lesions including those arising at fragile sites under replication stress. Here we demonstrate that H2AX is dynamically reorganized to preoccupy γH2AX hotspots on increased replication stress by activated cell proliferation and that H2AX is enriched in aphidicolin-induced replisome stalling sites in cycling cells. Interestingly, H2AX enrichment was particularly found in genomic regions that replicate in early S phase. High transcription activity, a hallmark of early replicating fragile sites, was a determinant of H2AX localization. Subtelomeric H2AX enrichment was also attributable to early replication and high gene density. In contrast, late replicating and infrequently transcribed regions, including common fragile sites and heterochromatin, lacked H2AX enrichment. In particular, heterochromatin was inaccessible to H2AX incorporation, maybe partly explaining the cause of mutation accumulation in cancer heterochromatin. Meanwhile, H2AX in actively dividing cells was intimately colocalized with INO80. INO80 silencing reduced H2AX levels, particularly at the INO80-enriched sites. Our findings suggest that active DNA replication is accompanied with the specific localization of H2AX and INO80 for efficient damage repair or replication-fork stabilization in actively transcribed regions.</P>

Regulation of the Boundaries of Accessible Chromatin

Chai, Xiaoran,Nagarajan, Sanjanaa,Kim, Kwoneel,Lee, Kibaick,Choi, Jung Kyoon Public Library of Science 2013 PLoS genetics Vol.9 No.9

<P>Regulatory regions maintain nucleosome-depleted, open chromatin status but simultaneously require the presence of nucleosomes for specific histone modifications. It remains unclear how these can be achieved for proper regulatory function. Here we demonstrate that nucleosomes positioned within accessible chromatin regions near the boundaries provide platforms for histone modifications while preventing the occlusion of regulatory elements. These boundary nucleosomes were particularly enriched for active or poised regulatory marks in human, such as histone acetylations, H3K4 methylations, H3K9me3, H3K79me2, and H4K20me1. Additionally, we found that based on a genome-wide profiling of ∼100 recombinant yeast strains, the location of open chromatin borders tends to vary mostly within 150 bp upon genetic perturbation whereas this positional variation increases in proportion to the sequence preferences of the underlying DNA for nucleosome formation. More than 40% of the local boundary shifts were associated with genetic variation in <I>cis</I>- or <I>trans</I>-acting factors. A sizeable fraction of the identified genetic factors was also associated with nearby gene expression, which was correlated with the distance between the transcription start site (tss) and the boundary that faces the tss. Taken together, the variation in the width of accessible chromatin regions may arise in conjunction with the modulation of the boundary nucleosomes by post-translational modifications or by chromatin regulators and in association with the activity of nearby gene transcription.</P><P><B>Author Summary</B></P><P>Open chromatin formation and regulation are intimately coupled with nucleosome remodelling and modification. Regulatory regions such as promoters and enhancers maintain nucleosome-free, open chromatin states whilst at the same time the presence of nucleosomes is required for specific histone modifications. In this work, we carried out detailed analyses of our data of open chromatin maps for ∼100 different yeast strains and whole-genome nucleosome occupancy along with the public data of open chromatin and nucleosome positioning in human generated in the ENCODE project. We observed nucleosomes positioned within accessible chromatin regions near their boundaries. These boundary nucleosomes appeared to carry various histone methylations without hampering the binding of DNA regulators and sequence preferences for these nucleosomes were associated with variation in the width of accessible chromatin. The end positions of open chromatin domains, particularly with high intrinsic preferences for nucleosome formation, were more flexible than the middle point, changing mostly within 150 bp upon genetic perturbation. By using quantitative trait loci (QTL) mapping, we identified genetic variants that are associated with the variation in the width of open chromatin and examined its relationship with nearby gene expression.</P>

Accelerated Evolution of the Regulatory Sequences of Brain Development in the Human Genome

Lee, Kang Seon,Bang, Hyoeun,Choi, Jung Kyoon,Kim, Kwoneel Korean Society for Molecular and Cellular Biology 2020 Molecules and cells Vol.43 No.4

Genetic modifications in noncoding regulatory regions are likely critical to human evolution. Human-accelerated noncoding elements are highly conserved noncoding regions among vertebrates but have large differences across humans, which implies human-specific regulatory potential. In this study, we found that human-accelerated noncoding elements were frequently coupled with DNase I hypersensitive sites (DHSs), together with monomethylated and trimethylated histone H3 lysine 4, which are active regulatory markers. This coupling was particularly pronounced in fetal brains relative to adult brains, non-brain fetal tissues, and embryonic stem cells. However, fetal brain DHSs were also specifically enriched in deeply conserved sequences, implying coexistence of universal maintenance and human-specific fitness in human brain development. We assessed whether this coexisting pattern was a general one by quantitatively measuring evolutionary rates of DHSs. As a result, fetal brain DHSs showed a mixed but distinct signature of regional conservation and outlier point acceleration as compared to other DHSs. This finding suggests that brain developmental sequences are selectively constrained in general, whereas specific nucleotides are under positive selection or constraint relaxation simultaneously. Hence, we hypothesize that human- or primate-specific changes to universally conserved regulatory codes of brain development may drive the accelerated, and most likely adaptive, evolution of the regulatory network of the human brain.