Focus 26 January 2021

Genetics, genomics and epigenetics

The accurate inheritance of phenotypes in all biological systems relies on the transmission of genetic and epigenetic information and failure in these operations often underlie many diseases. In this editorial page we explore exciting discoveries and technologies which push forward our understanding of genome organisation and evolution, rare and complex diseases and the molecular machines orchestrating these processes.

Featured articles

Multigenerational paternal obesity enhances the susceptibility to male subfertility in offspring via Wt1 N6-methyladenosine modification

The mechanisms through which multigenerational paternal obesity affects spermatogenesis in offspring remain poorly understood. Here, the authors show that it affects Wt1 m6A modifications, decreasing the fertility of offspring.
- Yong-Wei Xiong
- Hua-Long Zhu
- Hua Wang
ArticleOpen Access14 Feb 2024 Nature Communications
Two mitochondrial DNA polymorphisms modulate cardiolipin binding and lead to synthetic lethality

Chiang et al. map a genetic interaction in animal mitochondrial DNA by recombination. This reveals how polymorphisms in two complex IV subunits jointly affect cardiolipin binding to impact complex stability, organismal fitness and disease expression.
- Ason C. Y. Chiang
- Jan Ježek
- Hansong Ma
ArticleOpen Access19 Jan 2024 Nature Communications
Molecular quantitative trait loci in reproductive tissues impact male fertility in cattle

Investigating the genetics of male fertility requires comprehensive genotype and phenotype data. Here, the authors characterize the transcriptional complexity of bovine male reproductive tissues to identify loci associated with male fertility.
- Xena Marie Mapel
- Naveen Kumar Kadri
- Hubert Pausch
ArticleOpen Access22 Jan 2024 Nature Communications
Genetic separation of Brca1 functions reveal mutation-dependent Polθ vulnerabilities

Homologous recombination (HR) gene mutations are thought to be synthetic lethal with DNA polymerase theta (Polθ) inhibition. Here, the authors reveal that Polθ addiction is determined by the functional impact of gene mutations on DNA end resection activity.
- John J. Krais
- David J. Glass
- Neil Johnson
ArticleOpen Access24 Nov 2023 Nature Communications
The mutational landscape of the adult healthy parous and nulliparous human breast

While many tissues have been investigated for natural somatic mutations, human breast tissue has not been well studied. Here, the authors characterize somatic mutations in human breast tissue, finding effects of age and parity.
- Biancastella Cereser
- Angela Yiu
- Justin Stebbing
ArticleOpen Access6 Sep 2023 Nature Communications
ADRA2A and IRX1 are putative risk genes for Raynaud’s phenomenon

Raynaud’s phenomenon is a common vasospastic disorder, but the genetic origins of the condition are not well understood. Here, the authors find common genetic variants associated with Raynaud’s phenomenon, and find genes putatively involved in the disorder.
- Sylvia Hartmann
- Summaira Yasmeen
- Claudia Langenberg
ArticleOpen Access12 Oct 2023 Nature Communications
A deep population reference panel of tandem repeat variation

Tandem repeats (TRs) comprise some of the most polymorphic regions of the human genome but are difficult to study. Here, the authors develop an ensemble-based genotyping method and characterize 1.7 million TRs across 3,550 humans from diverse populations.
- Helyaneh Ziaei Jam
- Yang Li
- Melissa Gymrek
ArticleOpen Access23 Oct 2023 Nature Communications
Alternative splicing in lung influences COVID-19 severity and respiratory diseases

Alternative splicing of transcripts can influence human traits, such as immune response to infection. Here, the authors use mendelian randomization to reveal a role of alternative splicing in lung on COVID-19 severity and susceptibility, offering potential drug discovery avenues.
- Tomoko Nakanishi
- Julian Willett
- J. Brent Richards
ArticleOpen Access4 Oct 2023 Nature Communications
The genomic history of the indigenous people of the Canary Islands

Here, the authors use paleogenomic data from the indigenous people of the Canary Islands to shed light on the Prehistory of North Africa, and on how insularity and resources availability shaped the genetic composition of this isolated population.
- Javier G. Serrano
- Alejandra C. Ordóñez
- Rosa Fregel
ArticleOpen Access15 Aug 2023 Nature Communications
A spatio-temporally constrained gene regulatory network directed by PBX1/2 acquires limb patterning specificity via HAND2

Many key developmental transcriptional regulators are broadly expressed but perform distinct functions in specific tissues. Here they show that ubiquitously expressed PBX factors gain limb bud functionality by interaction with HAND2, uncovering fundamental principles of cooperation between promiscuous and tissue-specific regulators to instruct developmental programs.
- Marta Losa
- Iros Barozzi
- Licia Selleri
ArticleOpen Access6 Jul 2023 Nature Communications
Genome-wide host-pathogen analyses reveal genetic interaction points in tuberculosis disease

Few genetic loci have been associated with tuberculosis infection, possibly because of the influence of genetic variation in the pathogen. Here, the authors integrate human and Mycobacterium tuberculosis genetics to find genome-genome interactions associated with infection.
- Jody Phelan
- Paula Josefina Gomez-Gonzalez
- Taane G. Clark
ArticleOpen Access1 Feb 2023 Nature Communications
Characterization of genome-wide STR variation in 6487 human genomes

Short tandem repeat studies in humans have often focused on European populations. Here, the authors report a comprehensive map of 366,013 polymorphic short tandem repeats in Chinese individuals and their mutational patterns, functional properties, gene regulatory effects and population characteristics.
- Yirong Shi
- Yiwei Niu
- Shunmin He
ArticleOpen Access12 Apr 2023 Nature Communications
Higher-order epistasis shapes natural variation in germ stem cell niche activity

Stem cell niches regulate proliferation of stem cells, but variation in this control across natural populations has not been explored. Here they combine quantitative genetics and gene editing to show that natural variation in C. elegans germ stem cell niche activity is shaped by complex gene-gene interactions.
- Sarah R. Fausett
- Asma Sandjak
- Christian Braendle
ArticleOpen Access17 May 2023 Nature Communications
Transcription factor binding site orientation and order are major drivers of gene regulatory activity

Gene regulatory grammar remains difficult to decipher, hindering our ability to link genotype to phenotype. Here they use massively parallel reporter assays to test over 200,000 synthetic sequences, finding that transcription factor binding site order and orientation have a major effect on gene regulatory activity.
- Ilias Georgakopoulos-Soares
- Chengyu Deng
- Nadav Ahituv
ArticleOpen Access22 Apr 2023 Nature Communications
Combinatorial effects on gene expression at the Lbx1/Fgf8 locus resolve split-hand/foot malformation type 3

Congenital limb defects are often associated with genomic rearrangements. Here they provide insights into the molecular mechanism underlying SHFM3-associated structural variations, offering a conceptual framework for how genomic rearrangements can alter gene expression and cause disease.
- Giulia Cova
- Juliane Glaser
- Stefan Mundlos
ArticleOpen Access17 Mar 2023 Nature Communications
A maximum-entropy model to predict 3D structural ensembles of chromatin from pairwise distances with applications to interphase chromosomes and structural variants

Here the authors develop a computational method based on the maximum entropy principle to construct the structural ensemble of genomes using imaging data. The work reveals three-way contacts between loci and extensive conformational heterogeneity.
- Guang Shi
- D. Thirumalai
ArticleOpen Access1 Mar 2023 Nature Communications
Pivotal role for S-nitrosylation of DNA methyltransferase 3B in epigenetic regulation of tumorigenesis

Here the authors demonstrate that de novo DNA methylation mediated by DNMT3B is regulated by nitric oxide (NO). They also isolate a unique modulator (DBIC) that inhibits S-nitrosylation of DNMT3B, which mitigates cell proliferation and tumorigenic conversion in vivo.
- Kosaku Okuda
- Kengo Nakahara
- Takashi Uehara
ArticleOpen Access4 Feb 2023 Nature Communications
A CpG island-encoded mechanism protects genes from premature transcription termination

Here the authors discover that SET1 complexes function as transcription anti-termination factors that bind to CpG islands and protect low to moderately transcribed genes from the pervasive termination activity of the ZC3H4 complex.
- Amy L. Hughes
- Aleksander T. Szczurek
- Robert J. Klose
ArticleOpen Access9 Feb 2023 Nature Communications
Mechanistic insights into RNA surveillance by the canonical poly(A) polymerase Pla1 of the MTREC complex

Here the authors show how the MTREC core protein Red1 binds to and sequesters Pla1 from the 3’-end processing machinery to hyperadenylate cryptic unstable transcripts and target them to the exosome for efficient degradation.
- Komal Soni
- Anusree Sivadas
- Tamás Fischer
ArticleOpen Access11 Feb 2023 Nature Communications
H2B ubiquitination recruits FACT to maintain a stable altered nucleosome state for transcriptional activation

Here the authors investigated the direct collaboration between ubiquitinated histone H2B (ubH2B) with FACT at the nucleosome level. They found ubH2B enhances FACT’s chaperone property, recruits FACT to form a stable altered nucleosome state, and provides a key platform for transcription.
- Anfeng Luo
- Jingwei Kong
- Ping Chen
ArticleOpen Access10 Feb 2023 Nature Communications
Reanalysis of ribosome profiling datasets reveals a function of rocaglamide A in perturbing the dynamics of translation elongation via eIF4A

The compound Rocaglamide A (RocA) is known for repressing translation initiation. Here the authors identify a dual mode of action for RocA in blocking translation initiation and elongation via eIF4A using previous datasets and new analyses.
- Fajin Li
- Jianhuo Fang
- Xuerui Yang
ArticleOpen Access2 Feb 2023 Nature Communications
Replication gap suppression depends on the double-strand DNA binding activity of BRCA2

Here the authors demonstrate that the dsDNA binding function at the N-terminus of BRCA2 prevents nucleotide depletion-dependent replicative ssDNA gaps but not those induced by PARP inhibition. This function is impaired in breast-cancer variants affecting this region.
- Domagoj Vugic
- Isaac Dumoulin
- Aura Carreira
ArticleOpen Access27 Jan 2023 Nature Communications
SPRTN patient variants cause global-genome DNA-protein crosslink repair defects

DNA-protein crosslinks (DPCs) are toxic DNA lesions which threaten genome stability. Here, the authors develop a method to track the fate of DPCs in cells and identify a role for the SPRTN protease in replication-independent DPC repair.
- Pedro Weickert
- Hao-Yi Li
- Julian Stingele
ArticleOpen Access21 Jan 2023 Nature Communications
Exon junction complex shapes the m⁶A epitranscriptome

Here the authors show the exon junction complex (EJC) component, EIF4A3, locally restricts METTL3- mediated mRNA methylation at exon junctions to explain the observed widespread enrichment of m6A modification in 3’ untranslated regions.
- Xin Yang
- Robinson Triboulet
- Richard I. Gregory
ArticleOpen Access23 Dec 2022 Nature Communications
Reference panel guided topological structure annotation of Hi-C data

Predicting topological structures from Hi-C data provides insight into comprehending gene expression and regulation. Here, the authors present RefHiC, an attention-based deep learning framework that leverages a reference panel of Hi-C datasets to assist topological structure annotation from a given study sample.
- Yanlin Zhang
- Mathieu Blanchette
ArticleOpen Access2 Dec 2022 Nature Communications
Primate-specific transposable elements shape transcriptional networks during human development

The human genome harbors more than 4.5 million transposable element (TE)-derived insertions, the result of recurrent waves of invasion and internal propagation. Here they show that TEs belonging to evolutionarily recent subfamilies go on to regulate later stages of human embryonic development, notably conditioning the expression of genes involved in gastrulation and early organogenesis.
- Julien Pontis
- Cyril Pulver
- Didier Trono
ArticleOpen Access23 Nov 2022 Nature Communications
Nuclear localization of mitochondrial TCA cycle enzymes modulates pluripotency via histone acetylation

Cellular metabolism is important in pluripotency and cell fate regulation. Here, authors observe chromatin remodeling followed by TCA enzyme translocation from the mitochondria to the nucleus, demonstrating pluripotency regulation by mitochondria to nucleus retrograde signaling.
- Wei Li
- Qi Long
- Xingguo Liu
ArticleOpen Access2 Dec 2022 Nature Communications
Decoding the spatial chromatin organization and dynamic epigenetic landscapes of macrophage cells during differentiation and immune activation

Here the authors delineate the dynamic changes in 3D genome and epigenome of differentiating macrophages and during infection with Mycobacterium tuberculosis. They reveal a role for NF-κB upon infection and identify SNPs in disease-susceptible loci, including rs1873613 that is located in the anchor of a dynamic chromatin loop.
- Da Lin
- Weize Xu
- Gang Cao
ArticleOpen Access4 Oct 2022 Nature Communications
A hierarchical transcription factor cascade regulates enteroendocrine cell diversity and plasticity in Drosophila

Here the authors elucidate a simple transcription factor code that underlies the complex genetic specification of enteroendocrine cell (EE) subtypes, and reveal significant cellular plasticity amongst EE subtypes.
- Xingting Guo
- Yongchao Zhang
- Rongwen Xi
ArticleOpen Access31 Oct 2022 Nature Communications
Unscheduled DNA replication in G1 causes genome instability and damage signatures indicative of replication collisions

Reusswig et al. use engineered systems to force DNA replication in the G1 phase of the cell cycle. This unscheduled G1 replication shows hallmarks of S phase replication, but leads to over-replication and DNA breaks from replication collisions.
- Karl-Uwe Reusswig
- Julia Bittmann
- Boris Pfander
ArticleOpen Access18 Nov 2022 Nature Communications
Tissue-specific impacts of aging and genetics on gene expression patterns in humans

Age is a risk factor for many diseases, but the impact of aging on molecular phenotypes is not fully understood. Here, the authors quantify the relative contributions of genetics and aging to gene expression patterns across 27 tissues in humans, showing that age and genetics each play distinct roles in shaping expression phenotypes.
- Ryo Yamamoto
- Ryan Chung
- Peter H. Sudmant
ArticleOpen Access3 Oct 2022 Nature Communications
Clonal hematopoiesis of indeterminate potential, DNA methylation, and risk for coronary artery disease

Clonal hematopoiesis, often caused by mutations in DNMT3A and TET2, is associated with blood cancer and coronary artery disease. Here, the authors conduct an epigenome-wide association study, finding that clonal hematopoiesis caused by DNMT3A vs. TET2 mutations has directionally opposing changes in DNA methylation profiles, with both promoting stem cell self-renewal.
- M d Mesbah Uddin
- Ngoc Quynh H. Nguyen
- Karen N. Conneely
ArticleOpen Access12 Sep 2022 Nature Communications
Histone H3K36me2 and H3K36me3 form a chromatin platform essential for DNMT3A-dependent DNA methylation in mouse oocytes

DNMT3A is known to methylate DNA at histone H3 lysine 36 (H3K36me3)-marked transcriptionally active regions in mouse oocytes. Here the authors show that DNMT3A is also guided by H3K36me2 to methylate broad domains in genic and intergenic loci, as well as on the X chromosome. These two histone marks together comprise the minimal chromatin signature for global DNA methylation in mouse oocytes.
- Seiichi Yano
- Takashi Ishiuchi
- Hiroyuki Sasaki
ArticleOpen Access3 Aug 2022 Nature Communications
Balanced gene dosage control rather than parental origin underpins genomic imprinting

Here the authors investigate whether for imprinted genes the parent-of-origin of the expressed allele or rather appropriate gene dosage is more important for normal development. Using the differentially methylated region of Dlk1-Dio3 gene involved in imprinting, they show that correct parent-of-origin imprinting pattern is secondary to balanced gene dosage.
- Ariella Weinberg-Shukron
- Raz Ben-Yair
- Yonatan Stelzer
ArticleOpen Access29 Jul 2022 Nature Communications
Multiple parameters shape the 3D chromatin structure of single nuclei at the doc locus in Drosophila

Here the authors applied their recently developed multiplexed DNA-FISH Hi-M method to dissect the sources of heterogeneity in topologically associating domain (TAD)-like organization during Drosophila embryogenesis. This single-nucleus analysis allows them to reveal that multiple parameters contribute to shaping the trace of the chromatin path from a single nucleus.
- Markus Götz
- Olivier Messina
- Marcelo Nollmann
ArticleOpen Access14 Sep 2022 Nature Communications
A single WNT enhancer drives specification and regeneration of the Drosophila wing

The wing is a remarkable evolutionary novelty in insects. Here the authors demonstrate that the specification and regenerative capacity of the wing relies on a single wing-specific enhancer of the wingless gene in Drosophila.
- Elena Gracia-Latorre
- Lidia Pérez
- Marco Milán
ArticleOpen Access22 Aug 2022 Nature Communications
A reference single-cell regulomic and transcriptomic map of cynomolgus monkeys

Non-human primates are attractive laboratory animal models that can accurately reflect some developmental and pathological features of humans. Here the authors chart a reference cell map of cynomolgus monkeys using both scATAC-seq and scRNA-seq data across multiple organs, providing insights into the molecular dynamics and cellular heterogeneity of this organism.
- Jiao Qu
- Fa Yang
- Dijun Chen
ArticleOpen Access13 Jul 2022 Nature Communications
Chromatin sequesters pioneer transcription factor Sox2 from exerting force on DNA

Here the authors used single-molecule imaging and manipulation to study the mechanical effects of transcription factor Sox2 co-condensation with DNA and chromatin. They found that Sox2 condensates exert a high level of mechanical stress on DNA, but this stress is dramatically attenuated by nucleosomes assembled on the DNA.
- Tuan Nguyen
- Sai Li
- Shixin Liu
ArticleOpen Access9 Jul 2022 Nature Communications
Cohesin couples transcriptional bursting probabilities of inducible enhancers and promoters

Here the authors show inducible genes and enhancers are regulated mainly by transcriptional burst frequency and that this is coordinated in single cells and individual alleles. Cohesin, which is important for inducible gene expression, is largely dispensable for regulating enhancer burst frequencies; however, it is required for coupling burst frequencies of inducible enhancers and promoters.
- Irene Robles-Rebollo
- Sergi Cuartero
- Matthias Merkenschlager
ArticleOpen Access27 Jul 2022 Nature Communications
HSF1 phosphorylation establishes an active chromatin state via the TRRAP–TIP60 complex and promotes tumorigenesis

Here the authors show phosphorylation of heat shock factor 1 (HSF1) at S419 via the chromatin-bound kinase PLK1, promotes HSF1 recruitment of histone acetyltransferases and histone acetylation reader proteins TRIM33 and TRIM24, which actually also execute histone H2BK120 mono-ubiquitination at target genes. Furthermore, HSF1 phosphorylation has an impact on melanoma cell proliferation.
- Mitsuaki Fujimoto
- Ryosuke Takii
- Akira Nakai
ArticleOpen Access29 Jul 2022 Nature Communications
Small RNA pathways in the nematode Ascaris in the absence of piRNAs

The parasitic nematode Ascaris lacks piRNAs. Here the authors compare Argonaute proteins and small RNAs from C. elegans and Ascaris, expanding our understanding of the conservation, divergence, and flexibility of Argonautes and small RNA pathways in nematodes.
- Maxim V. Zagoskin
- Jianbin Wang
- Richard E. Davis
ArticleOpen Access11 Feb 2022 Nature Communications
Pluripotency factors determine gene expression repertoire at zygotic genome activation

Zygotic genome activation in zebrafish relies on pluripotency transcription factors Pou5f3 and Sox19b. Here the authors investigate how these factors interact in vivo by analyzing the changes in chromatin state and time-resolved transcription in Pou5f3 and Sox19b single and double mutant embryos.
- Meijiang Gao
- Marina Veil
- Daria Onichtchouk
ArticleOpen Access10 Feb 2022 Nature Communications
A mammalian methylation array for profiling methylation levels at conserved sequences

Methods to probe DNA methylation in the majority of non-human mammals are lacking. Here the authors developed a Mammalian Methylation Array that includes 36k well-conserved CpGs in mammals which will facilitate cross-species comparisons. They annotate the conserved CpGs in > 200 species. The array allows one to measure methylation in all mammalian species including unsequenced ones.
- Adriana Arneson
- Amin Haghani
- Steve Horvath
ArticleOpen Access10 Feb 2022 Nature Communications
Dynamic Runx1 chromatin boundaries affect gene expression in hematopoietic development

RUNX1 is a large and complex gene with two alternative promoters and multiple hematopoietic enhancers. Here the authors show that unlike smaller genes Runx1 becomes sub-compartmentalized during differentiation and gene activation. This subcompartmentalization partially depends on CTCF binding at promoter-proximal CTCF sites and transcription.
- Dominic D. G. Owens
- Giorgio Anselmi
- Marella F. T. R. de Bruijn
ArticleOpen Access9 Feb 2022 Nature Communications
Pre-configuring chromatin architecture with histone modifications guides hematopoietic stem cell formation in mouse embryos

Here, the authors employed Hi-C and low-input itChIP-seq in four rare populations of the hematopoietic stem cell (HSC) ontogeny trajectory across early arterial endothelial cells (eAECs), hemogenic endothelial cells (HECs), pre-HSCs, and long-term HSCs (LT-HSCs) from mouse embryos to show that active histone modifications are largely set up in eAECs and 3D genome is then subsequently configured.
- Chen C. Li
- Guangyu Zhang
- Aibin He
ArticleOpen Access17 Jan 2022 Nature Communications
Investigating the shared genetic architecture between multiple sclerosis and inflammatory bowel diseases

An epidemiological association between multiple sclerosis (MS) and inflammatory bowel disease (IBD) is well-established, but a genetic link is unclear. Here, the authors investigate the shared genetic architecture between MS and IBD to shed light on the biological basis of comorbidity.
- Yuanhao Yang
- Hannah Musco
- Yuan Zhou
ArticleOpen Access24 Sep 2021 Nature Communications
Nanopore sequencing of brain-derived full-length circRNAs reveals circRNA-specific exon usage, intron retention and microexons

Short-read sequencing methods cannot delineate internal exon composition and alternative splicing events of long and multi-exon circular RNAs (circRNAs). Here the authors provide a global map of full-length circRNAs by long-read sequencing in human and mouse brain samples.
- Karim Rahimi
- Morten T. Venø
- Jørgen Kjems
ArticleOpen Access10 Aug 2021 Nature Communications
Global view on the metabolism of RNA poly(A) tails in yeast Saccharomyces cerevisiae

RNA polyadenosine tails are important for the export, translation and stability of mRNAs and play a role in non-coding RNA biogenesis. Here the authors measure yeast poly(A) tail lengths by direct RNA sequencing, revealing its dynamics in yeast exonuclease, deadenylase and poly(A) polymerase mutants.
- Agnieszka Tudek
- Paweł S. Krawczyk
- Andrzej Dziembowski
ArticleOpen Access16 Aug 2021 Nature Communications
Somatic genetic rescue of a germline ribosome assembly defect

Shwachman-Diamond syndrome (SDS) is a leukemia predisposition disorder that is caused by defective release of eIF6 during ribosome assembly. Here the authors show that acquired somatic EIF6 mutations are frequent in the hematopoietic cells from individuals with SDS and provide a selective advantage over non-modified cells.
- Shengjiang Tan
- Laëtitia Kermasson
- Patrick Revy
ArticleOpen Access19 Aug 2021 Nature Communications
The regulatory impact of RNA-binding proteins on microRNA targeting

miRNAs are loaded into Argonaute protein and repress complementary mRNA targets. Here the authors show the unappreciated role of RNA binding proteins for efficient miRNA targeting and expand the current understanding of miRNA targeting.
- Sukjun Kim
- Soyoung Kim
- Daehyun Baek
ArticleOpen Access20 Aug 2021 Nature Communications

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