Distal Gene Research Articles

Red Light/Green Light, a Dual Fluorescent Protein Reporter System To Study Enhancer-Promoter Specificity in Drosophila.

Enhancers activate gene transcription in spatial and temporal patterns by interactions with gene promoters. These elements typically reside distal to their target promoter, with which they must interact selectively. Additional elements may contribute to enhancer-promoter specificity, including remote control element sequences within enhancers, tethering elements near promoters, and insulator/boundary elements that disrupt off-target interactions. However, few of these elements have been mapped, and as a result, the mechanisms by which these elements interact remain poorly understood. One impediment is their method of study, namely reporter transgenes in which enhancers are placed adjacent to a heterologous promoter, which may circumvent mechanisms controlling enhancer-promoter specificity and long-range interactions. Here, we report an optimized dual reporter transgene system in Drosophila melanogaster that allows the simultaneous comparison of an enhancer’s ability to activate proximal and distal fluorescent reporter genes. Testing a panel of fluorescent transgenes in vivo, we found a two-protein combination that allows simultaneous measurement with minimal detection interference. We note differences among four tested enhancers in their ability to regulate a distally placed reporter transgene. These results suggest that enhancers differ in their requirements for promoter interaction and raise important practical considerations when studying enhancer function.

CDK-Mediator and FBXL19 prime developmental genes for activation by promoting atypical regulatory interactions.

Appropriate developmental gene regulation relies on the capacity of gene promoters to integrate inputs from distal regulatory elements, yet how this is achieved remains poorly understood. In embryonic stem cells (ESCs), a subset of silent developmental gene promoters are primed for activation by FBXL19, a CpG island binding protein, through its capacity to recruit CDK-Mediator. How mechanistically these proteins function together to prime genes for activation during differentiation is unknown. Here we discover that in mouse ESCs FBXL19 and CDK-Mediator support long-range interactions between silent gene promoters that rely on FBXL19 for their induction during differentiation and gene regulatory elements. During gene induction, these distal regulatory elements behave in an atypical manner, in that the majority do not acquire histone H3 lysine 27 acetylation and no longer interact with their target gene promoter following gene activation. Despite these atypical features, we demonstrate by targeted deletions that these distal elements are required for appropriate gene induction during differentiation. Together these discoveries demonstrate that CpG-island associated gene promoters can prime genes for activation by communicating with atypical distal gene regulatory elements to achieve appropriate gene expression.

Using regulatory variants to detect gene\u2013gene interactions identifies networks of genes linked to cell immortalisation

The extent to which the impact of regulatory genetic variants may depend on other factors, such as the expression levels of upstream transcription factors, remains poorly understood. Here we report a framework in which regulatory variants are first aggregated into sets, and using these as estimates of the total cis-genetic effects on a gene we model their non-additive interactions with the expression of other genes in the genome. Using 1220 lymphoblastoid cell lines across platforms and independent datasets we identify 74 genes where the impact of their regulatory variant-set is linked to the expression levels of networks of distal genes. We show that these networks are predominantly associated with tumourigenesis pathways, through which immortalised cells are able to rapidly proliferate. We consequently present an approach to define gene interaction networks underlying important cellular pathways such as cell immortalisation.

R-Loop Mediated trans Action of the APOLO Long Noncoding RNA.

In eukaryotes, three-dimensional genome organization is critical for transcriptional regulation of gene expression. Long noncoding RNAs (lncRNAs) can modulate chromatin conformation of spatially related genomic locations within the nucleus. Here, we showthat the lncRNA APOLO (AUXIN-REGULATED PROMOTER LOOP) recognizes multiple distant independent loci in the Arabidopsis thaliana genome. We found that APOLO targets are not spatially associated in the nucleus and that APOLO recognizes its targets by short sequence complementarity and theformation of DNA-RNA duplexes (R-loops). The invasion of APOLO to the target DNA decoys the plant Polycomb Repressive Complex 1 component LHP1, modulating local chromatin 3D conformation. APOLO lncRNA coordinates the expression of distal unrelated auxin-responsive genes during lateral root development in Arabidopsis. Hence, R-loop formation and chromatin protein decoy mediate trans action of lncRNAs on distant loci. VIDEO ABSTRACT.

Venomic Interrogation Reveals the Complexity of Conus striolatus Venom

Given the complexity of cone snail venoms, high throughput venomics approaches are required to fully investigate venom composition, envenomation strategies, and evolutionary trajectories. This study describes 158 conotoxins in the venom transcriptome of the little studied C. striolatus from the fish hunting clade Pionoconus. Despite similar gene superfamily distributions along the venom duct, only 18 common transcripts were identified between distal, central, and proximal venom duct transcriptomes. Proteomic analysis of the injected predatory venom collected from the same individual revealed an ~18-fold enhanced complexity at the proteomic level, consistent with complex post-translational modifications and variable venom peptide processing occurring in the venom duct. Overall, C. striolatus venom was dominated by M, O1, O2, and A gene superfamily conotoxins and conkunitzins, which are potential modulators of sodium, calcium, and potassium channels. Conkunitzins and gene superfamily A peptides dominated the proximal over the distal duct, the M and O1 gene superfamily peptides were distributed along the full length of the duct, while the O2 gene superfamily peptides dominated the distal duct. Interestingly, the predatory injected venom of C. striolatus was dominated by peptides from gene superfamilies M, O1, O2, A, and conkunitzins, suggesting the predatory venom of C. striolatus may arise at multiple sites along the venom duct.

Prioritizing long range interactions in noncoding regions using GWAS and deletions perturbed TADs

Genome-wide association studies (GWAS) have contributed significantly to predisposing the disease etiology by associating single nucleotide polymorphisms (SNPs) with complex diseases. However, most GWAS-SNPs are in the noncoding regions that may affect distal genes via long range enhancer-promoter interactions. Thus, the common practice on GWAS discoveries cannot fully reveal the molecular mechanisms underpinning complex diseases. It is known that perturbations of topological associated domains (TADs) lead to long range interactions which underlie disease etiology. To identify the probable long range interactions in noncoding regions via GWAS and TADs perturbed by deletions, we integrated datasets from GWAS-SNPs, enhancers, TADs, and deletions. After ranking and clustering, we prioritized 201,132 high confident pairs of GWAS-SNPs and target genes. In this study, we performed a systematic inference on noncoding regions via GWAS-SNPs and deletion-perturbed TADs to boost GWAS discovery power. The high confident pairs of GWAS-SNPs and target genes (SE-Gs) provide the promising candidates to understand the molecular mechanisms underlying complex diseases with emphasis on the three-dimensional genome.

Patterns of diverse gene functions in genomic neighborhoods predict gene function and phenotype

Genes with similar roles in the cell cluster on chromosomes, thus benefiting from coordinated regulation. This allows gene function to be inferred by transferring annotations from genomic neighbors, following the guilt-by-association principle. We performed a systematic search for co-occurrence of >1000 gene functions in genomic neighborhoods across 1669 prokaryotic, 49 fungal and 80 metazoan genomes, revealing prevalent patterns that cannot be explained by clustering of functionally similar genes. It is a very common occurrence that pairs of dissimilar gene functions – corresponding to semantically distant Gene Ontology terms – are significantly co-located on chromosomes. These neighborhood associations are often as conserved across genomes as the known associations between similar functions, suggesting selective benefits from clustering of certain diverse functions, which may conceivably play complementary roles in the cell. We propose a simple encoding of chromosomal gene order, the neighborhood function profiles (NFP), which draws on diverse gene clustering patterns to predict gene function and phenotype. NFPs yield a 26–46% increase in predictive power over state-of-the-art approaches that propagate function across neighborhoods, thus providing hundreds of novel, high-confidence gene function inferences per genome. Furthermore, we demonstrate that copy number-neutral structural variation that shapes gene function distribution across chromosomes can predict phenotype of individuals from their genome sequence.

Solving the controversy of healthier organic fruit: Leaf wounding triggers distant gene expression response of polyphenol biosynthesis in strawberry fruit (Fragaria x ananassa)

The claim that organic agriculture produces higher levels of phytochemicals has been controversial for decades. Using strawberries as a model crop in field conditions, a preharvest leaf wounding stress was applied to study the production of phytochemicals in fruits. As a result phenolic compounds (PCs) and total soluble sugars increased significantly, where specific phenylpropanoids showed increment up to 137% and several genes related to PCs biosynthesis and sugar transport were overexpressed. It was observed that the accumulation of PCs on fruits can be triggered by the application of wounding stress in a distant tissue and this accumulation is directly related to carbon partition and associated gene expression. This supports the idea that higher levels of healthy phytochemicals reported in organic fruits and vegetables could be due to the wounding component of the biotic stress attributed to insects to which the plant are exposed to.

TFIIIC Binding to Alu Elements Controls Gene Expression via Chromatin Looping and Histone Acetylation.

SummaryHow repetitive elements, epigenetic modifications, and architectural proteins interact ensuring proper genome expression remains poorly understood. Here, we report regulatory mechanisms unveiling a central role of Alu elements (AEs) and RNA polymerase III transcription factor C (TFIIIC) in structurally and functionally modulating the genome via chromatin looping and histone acetylation. Upon serum deprivation, a subset of AEs pre-marked by the activity-dependent neuroprotector homeobox Protein (ADNP) and located near cell-cycle genes recruits TFIIIC, which alters their chromatin accessibility by direct acetylation of histone H3 lysine-18 (H3K18). This facilitates the contacts of AEs with distant CTCF sites near promoter of other cell-cycle genes, which also become hyperacetylated at H3K18. These changes ensure basal transcription of cell-cycle genes and are critical for their re-activation upon serum re-exposure. Our study reveals how direct manipulation of the epigenetic state of AEs by a general transcription factor regulates 3D genome folding and expression.

Genetics of Gene Expression in the Aging Human Brain Reveal TDP-43 Proteinopathy Pathophysiology

Genetic variants that control multiple distant gene expressions are highly relevant for disease mechanisms. Here, in the aging human brain, we perform genome-wide screen of variants that regulate the average expression of each gene co-expression network and identify such variants in TMEM106B and RBFOX1 loci. The TMEM106 Blocus coincides with a known TDP-43 proteinopathy risk haplotype, and shows large-scale transcriptomic effects including lysosomal dysregulation and altered synaptic gene splicing, that capture TDP-43 proteinopathy pathophysiology. Further, a locus in GRN, another TDP-43 proteinopathy risk gene, shows concordant effects with the TMEM106B locus. Leveraging neuropathology data from the same participants, we also show that TMEM106B and APOE/amyloid-β effects converge to alter myelination/lysosomal gene expression, which then contributes to TDP-43 accumulation. These results advance our mechanistic understanding of the TMEM106B TDP-43 risk allele, and uncover a transcriptional program that mediates APOE/amyloid-β and TMEM106B effects on TDP-43 aggregation in older adults.

TRAV gene segments further away from the TRAJ gene segment cluster appear more commonly in human tumor and blood samples

We considered the possibility that the greater the distance between an immune receptor V and J, the more likely the V usage. Such a hypothesis is supported by results from mouse experiments. And, such a hypothesis is consistent with the fundamental nature of recombination and genomic distance: the further the distance, the greater the chance of a DNA break. Thus, we exploited the vast dataset of V and J recombination reads available for the human TRA gene, particularly from cancer and blood specimens, to assess the frequency of TRAV usage with respect to distance from the TRAJ cluster. Results indicated that, indeed, over the entire TRAV cluster, there is a greater chance of V usage the further the distance from the J cluster. These results do not address causation, and are not consistent for certain individual V gene segments, but the results do indicate that overall, the larger the distance between the V and J gene segment cluster, the more likely the appearance of at least a subset of TRAV segments, particularly among tumor infiltrating lymphocytes. With a similar approach, the distal TRAV gene segments were also found to be more commonly associated with a subset of distal TRAJ segments. These results have implications for restrictions on the apparent TRA repertoire in disease settings.

Whole exome sequencing identified ATP6V1C2 as a novel candidate gene for recessive distal renal tubular acidosis

Distal renal tubular acidosis is a rare renal tubular disorder characterized by hyperchloremic metabolic acidosis and impaired urinary acidification. Mutations in three genes (ATP6V0A4, ATP6V1B1 and SLC4A1) constitute a monogenic causation in 58-70% of familial cases of distal renal tubular acidosis. Recently, mutations in FOXI1 have been identified as an additional cause. Therefore, we hypothesized that further monogenic causes of distal renal tubular acidosis remain to be discovered. Panel sequencing and/or whole exome sequencing was performed in a cohort of 17 families with 19 affected individuals with pediatric onset distal renal tubular acidosis. A causative mutation was detected in one of the three "classical" known distal renal tubular acidosis genes in 10 of 17 families. The seven unsolved families were then subjected to candidate whole exome sequencing analysis. Potential disease causing mutations in three genes were detected: ATP6V1C2, which encodes another kidney specific subunit of the V-type proton ATPase (1 family); WDR72 (2 families), previously implicated in V-ATPase trafficking in cells; and SLC4A2 (1 family), a paralog of the known distal renal tubular acidosis gene SLC4A1. Two of these mutations were assessed for deleteriousness through functional studies. Yeast growth assays for ATP6V1C2 revealed loss-of-function for the patient mutation, strongly supporting ATP6V1C2 as a novel distal renal tubular acidosis gene. Thus, we provided a molecular diagnosis in a known distal renal tubular acidosis gene in 10 of 17 families (59%) with this disease, identified mutations in ATP6V1C2 as a novel human candidate gene, and provided further evidence for phenotypic expansion in WDR72 mutations from amelogenesis imperfecta to distal renal tubular acidosis.

Comprehensive analysis of long noncoding RNA (lncRNA)-chromatin interactions reveals lncRNA functions dependent on binding diverse regulatory elements

Over the past decade, thousands of long noncoding RNAs (lncRNAs) have been identified, many of which play crucial roles in normal physiology and human disease. LncRNAs can interact with chromatin and then recruit protein complexes to remodel chromatin states, thus regulating gene expression. However, how lncRNA-chromatin interactions contribute to their biological functions is largely unknown. Here, we collected and constructed an atlas of 188,647 lncRNA-chromatin interactions in human and mouse. All lncRNAs showed diverse epigenetic modification patterns at their binding sites, especially the marks of enhancer activity. Functional analysis of lncRNA target genes further revealed that lncRNAs could exert their functions by binding to both promoter and distal regulatory elements, especially the distal regulatory elements. Intriguingly, many important pathways were observed to be widely regulated by lncRNAs through distal binding. For example, NEAT1, a cancer lncRNA, controls 13.3% of genes in the PI3K-AKT signaling pathway by interacting with distal regulatory elements. In addition, "two-gene" signatures composed of a lncRNA and its distal target genes, such as HOTAIR-CRIM1, provided significant clinical benefits relative to the lncRNA alone. In summary, our findings underscored that lncRNA-distal interactions were essential for lncRNA functions, which would provide new clues to understand the molecular mechanisms of lncRNAs in complex disease.

Conserved structure of the NPR1 gene distal promoter isolated from a chili pepper (Capsicum annuum L.) in West Sumatera

Background: The non-expressor of pathogenesis related gene 1 (NPR1) protein is one of the key regulators in the systemic acquired resistance plant defense system. The cis-acting elements of its distal promoter gene are characterized by salicylic acid inducing elements such as the W-box, RAV1AAT and ASF1, accompanied by enhancer and silencer elements. This study was aimed to isolate and characterize the distal promoter sequence of the NPR1 gene (PD_CbNPR1) from the chili pepper (Capsicum annuum L.) genotype Berangkai, a local genotype known to produce large yields, but is susceptible to viral infection. Elucidating its sequence structure will open a broad range of possibilities to engineer the NPR1 gene expression which is important to improve chili pepper resistant. Methods: PCR-based cloning combined with a primer walking strategy was applied in this study. The BioEdit tool was used to edit the sequence and verify sequence integrity, while homology analysis was conducted with BLASTn searching. Identification of a cis-acting element was detected by PLACE, PlantCare, and PlantPAN. Results: Isolation of the complete distal promoter sequence of PD_CbNPR1 produced a fragment 5,950 bp in size. BLASTn search analysis indicated that PD_CbNPR1 sequence is highly conserved (99% identity) showing only a single nucleotide polymorphism (SNP) (base substitution) compared with its reference sequence. Analysis using PLACE tools successfully identified nine cis-acting elements containing a W-box, WLE1, RAV1AAT, TATA-box, CAAT-box, GARE and GT1 with multi repeats and diverse motives, as well as enhancer and silencer elements, which is characterized by a CCAAT-box and GAGAAATT pattern, respectively. Conclusion: The distal promoter of the NPR1 gene is highly conserved, showing only one SNP caused by one base substitution event.

In silico analysis of human renin gene-gene interactions and neighborhood topologically associated domains suggests breakdown of insulators contribute to ageing-associated diseases.

Three-dimensional chromatin architecture and gene-gene interactions impact gene expression. We assembled this information, in silico, for the human renin gene (REN). We searched for chromatin contacts and boundaries and the locations of super-enhancers that are involved in cell specific differentiation. The REN promoter was connected via RNA polymerase II binding to promoters of 12 neighboring genes on chromosome 1q32.1 over a distance of 762,497bp. This constitutes a regulatory archipelago. The genes formed 3 topologically associated domains (TADs), as follows: TAD1: ZC3H11A, SNRPE, LINC00303; SOX13; TAD2: ETNK2, REN, KISS1, GOLT1A; TAD3: PLEKHA6, LINC00628, PPP1R15B, PIK3C2B, MDM4. REN in TAD2, was isolated from its neighboring genes in TAD1 and TAD3 by CTCF-binding sites that serve as insulators. TAD1 and TAD3 genes SOX13 and LINC00628 overlapped super-enhancers, known to reside near nodes regulating cell identity, and were co-expressed in various tissues, suggesting co-regulation. REN was also connected with 62 distant genes genome-wide, including the angiotensin II type 1 receptor gene. The findings lead us to invoke the following novel hypothesis. While the REN promoter is isolated from neighboring super-enhancers in most cells by insulators, these insulators break down with cell age to permit the inappropriate expression of REN in non-kidney cells by using the neighboring super-enhancers, resulting in expression in a wider spectrum of tissues, contributing to aging-related immune system dysregulation, cardiovascular diseases and cancers. Research is needed to confirm this hypothesis experimentally.

An Allele-Specific Functional SNP Associated with Two Systemic Autoimmune Diseases Modulates IRF5 Expression by Long-Range Chromatin Loop Formation

Both systemic lupus erythematosus (SLE) and systemic sclerosis (SSc) are autoimmune diseases sharing similar genetic backgrounds. Genome-wide association studies have constantly disclosed numerous genetic variants conferring to both disease risks at 7q32.1, but the functional mechanisms underlying them are still largely unknown. Through a series of bioinformatics and functional analyses, we prioritized a potential independent functional single-nucleotide polymorphism (rs13239597) within TNPO3 promoter region, residing in a putative enhancer element and validated that IRF5 is the distal target gene (∼118 kb) of rs13239597, which is a key regulator involved in pathogenic autoantibody dysregulation, increasing risk of both SLE and SSc. We experimentally validated the long-range chromatin interactions between rs13239597 and IRF5 using chromosome conformation capture assay. We further demonstrated that rs13239597-A acted as an allele-specific enhancer regulating IRF5 expression, independently of TNPO3 by using dual-luciferase reporter assays and CRISPR-Cas9. Particularly, the transcription factor EVI1 could preferentially bind to rs13239597-A allele and increase the enhancer activity to regulate IRF5 expression. Taken together, our results uncovered a mechanistic insight of a noncoding functional variant acting as an allele-specific distal enhancer to directly modulate IRF5 expression, which might obligate in understanding of complex genetic architectures of SLE and SSc pathogenesis.

Endocrine regulation of multichromatic color vision

Vertebrate color vision requires spectrally selective opsin-based pigments, expressed in distinct cone photoreceptor populations. In primates and in fish, spectrally divergent opsin genes may reside in head-to-tail tandem arrays. Mechanisms underlying differential expression from such arrays have not been fully elucidated. Regulation of human red (LWS) vs. green (MWS) opsins is considered a stochastic event, whereby upstream enhancers associate randomly with promoters of the proximal or distal gene, and one of these associations becomes permanent. We demonstrate that, distinct from this stochastic model, the endocrine signal thyroid hormone (TH) regulates differential expression of the orthologous zebrafish lws1/lws2 array, and of the tandemly quadruplicated rh2-1/rh2-2/rh2-3/rh2-4 array. TH treatment caused dramatic, dose-dependent increases in abundance of lws1, the proximal member of the lws array, and reduced lws2 Fluorescent lws reporters permitted direct visualization of individual cones switching expression from lws2 to lws1 Athyroidism increased lws2 and reduced lws1, except within a small ventral domain of lws1 that was likely sustained by retinoic acid signaling. Changes in lws abundance and distribution in athyroid zebrafish were rescued by TH, demonstrating plasticity of cone phenotype in response to this signal. TH manipulations also regulated the rh2 array, with athyroidism reducing abundance of distal members. Interestingly, the opsins encoded by the proximal lws gene and distal rh2 genes are sensitive to longer wavelengths than other members of their respective arrays; therefore, endogenous TH acts upon each opsin array to shift overall spectral sensitivity toward longer wavelengths, underlying coordinated changes in visual system function during development and growth.

The Airn lncRNA does not require any DNA elements within its locus to silence distant imprinted genes.

Long non-coding (lnc) RNAs are numerous and found throughout the mammalian genome, and many are thought to be involved in the regulation of gene expression. However, the majority remain relatively uncharacterised and of uncertain function making the use of model systems to uncover their mode of action valuable. Imprinted lncRNAs target and recruit epigenetic silencing factors to a cluster of imprinted genes on the same chromosome, making them one of the best characterized lncRNAs for silencing distant genes in cis. In this study we examined silencing of the distant imprinted gene Slc22a3 by the lncRNA Airn in the Igf2r imprinted cluster in mouse. Previously we proposed that imprinted lncRNAs may silence distant imprinted genes by disrupting promoter-enhancer interactions by being transcribed through the enhancer, which we called the enhancer interference hypothesis. Here we tested this hypothesis by first using allele-specific chromosome conformation capture (3C) to detect interactions between the Slc22a3 promoter and the locus of the Airn lncRNA that silences it on the paternal chromosome. In agreement with the model, we found interactions enriched on the maternal allele across the entire Airn gene consistent with multiple enhancer-promoter interactions. Therefore, to test the enhancer interference hypothesis we devised an approach to delete the entire Airn gene. However, the deletion showed that there are no essential enhancers for Slc22a2, Pde10a and Slc22a3 within the Airn gene, strongly indicating that the Airn RNA rather than its transcription is responsible for silencing distant imprinted genes. Furthermore, we found that silent imprinted genes were covered with large blocks of H3K27me3 on the repressed paternal allele. Therefore we propose an alternative hypothesis whereby the chromosome interactions may initially guide the lncRNA to target imprinted promoters and recruit repressive chromatin, and that these interactions are lost once silencing is established.

Abstract 3380: Methylome analysis of non-alcoholic fatty liver disease-associated hepatocellular carcinoma reveals etiology-specic pathway perturbations

Abstract Chronic hepatitis B infection (HBV) and non-alcoholic fatty liver disease (NAFLD) have been shown to induce aberrant DNA methylation that may contribute to the development of hepatocellular carcinoma (HCC), which is one of the most common liver cancers. Most previous studies on DNA methylation in HCC have focused on altered methylation at gene promoters and CpG islands/shores. However, it has been increasingly recognized that DNA methylation in other genomic regions, including distal enhancers and gene bodies, could also play important roles in gene regulation in cancers. In our whole-genome bisulfite sequencing (WGBS) analysis of 10 human HBV-associated tumors and 10 human NAFLD-associated tumors, methylation states at all CpG sites in the genome of HCC tumors are comprehensively studied. To see how the methylomes of these two groups of HCC samples are related to other liver-related normal and pathogenic samples, we collected published WGBS data for HCC tumor, tumor adjacent and normal liver samples. Global hypermethylation of NAFLD-HCC has been identified compared with HBV-HCC and differentially methylated regions in enhancer and gene body regions also have been detected. Different methylation patterns for HCC pathogenesis with different etiologies have been detected and may offer potentially more specific therapeutic targets. This project is supported by Collaborative Research Fund C4017-14G and the Focused Innovations Scheme 1907309. Citation Format: Qiong Wu. Methylome analysis of non-alcoholic fatty liver disease-associated hepatocellular carcinoma reveals etiology-specic pathway perturbations [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3380.

Intrachromosomal regulation decay in breast cancer

Abstract Biological systems exhibit unique phenotypes as the result of the expression of a genomic program. The regulation of this program is a complex phenomenon, wherein different regulatory mechanisms are involved. The deregulation of this program is at the centre of the emergence of diseases such as breast cancer. In particular, it has been observed that coregulation patterns between physically distant genes are lost in breast cancer. In this work, we present a systematic study of chromosome-wide gene coregulation patterns in breast cancer as inferred by information theoretical measures over large (whole-genome expression in several hundred transcriptomes) experimental data corpora. We analyzed the chromosomal distance decay of correlations and found it to be with fat-tail distribution in breast cancer while being fundamentally constant in nontumour samples. After model discrimination analyses, we concluded that the behaviour of the breast cancer distributions belongs to an intermediate regime between power law and Weibull distributions, with distinctive contributions corresponding to different chromosomes. This behaviour may have biological implications in terms of the organization of the gene regulatory program, and the changes found in this program between health and disease.