Circadian plasticity evolves through regulatory changes in a neuropeptide gene

Michael P Shahandeh ^1 2, Liliane Abuin ³, Lou Lescuyer De Decker ³, Julien Cergneux ³, Rafael Koch ⁴, Emi Nagoshi ⁴, Richard Benton ⁵

. 2024 Oct 16.

• PMID: 39415010
• DOI: 10.1038/s41586-024-08056-x

Abstract

Many organisms, including cosmopolitan drosophilids, show circadian plasticity, varying their activity with changing dawn-dusk intervals¹. How this behaviour evolves is unclear. Here we compare Drosophila melanogaster with Drosophila sechellia, an equatorial, ecological specialist that experiences minimal photoperiod variation, to investigate the mechanistic basis of circadian plasticity evolution². D. sechellia has lost the ability to delay its evening activity peak time under long photoperiods. Screening of circadian mutants in D. melanogaster/D. sechellia hybrids identifies a contribution of the neuropeptide pigment-dispersing factor (Pdf) to this loss. Pdf exhibits species-specific temporal expression, due in part to cis-regulatory divergence. RNA interference and rescue experiments in D. melanogaster using species-specific Pdf regulatory sequences demonstrate that modulation of this neuropeptide’s expression affects the degree of behavioural plasticity. The Pdf regulatory region exhibits signals of selection in D. sechellia and across populations of D. melanogaster from different latitudes. We provide evidence that plasticity confers a selective advantage for D. melanogaster at elevated latitude, whereas D. sechellia probably suffers fitness costs through reduced copulation success outside its range. Our findings highlight this neuropeptide gene as a hotspot locus for circadian plasticity evolution that might have contributed to both D. melanogaster’s global distribution and D. sechellia’s specialization.

Protocol for detecting genomic insulators in Drosophila using insulator-seq, a massively parallel reporter assay

Anastasiia Tonelli ¹, Pascal Cousin ², Maria Cristina Gambetta ³

 2024 Oct 24;5(4):103391.

• PMID: 39453817
• DOI: 10.1016/j.xpro.2024.103391

Free article

Abstract

Genomic insulators are DNA elements that prevent transcriptional activation of a promoter by an enhancer when interposed. We present a protocol for insulator-seq that enables high-throughput screening of genomic insulators using a plasmid-based massively parallel reporter assay in Drosophila cultured cells. We describe steps for insulator reporter plasmid library generation, transient transfection into cultured cells, and sequencing library preparation and provide a pipeline for data analysis. For complete details on the use and execution of this protocol, please refer to Tonelli et al.¹.

The LIDPAD Mouse Model Captures the Multisystem Interactions and Extrahepatic Complications in MASLD

Zun Siong Low ¹, Damien Chua ¹, Hong Sheng Cheng ¹, Rachel Tee ¹, Wei Ren Tan ¹, Christopher Ball ², Norliza Binte Esmail Sahib ¹, Ser Sue Ng ¹, Jing Qu ³, Yingzi Liu ⁴, Haiyu Hong ⁵, Chaonong Cai ⁵, Nandini Chilagondanahalli Lakshmi Rao ⁶, Aileen Wee ⁷, Mark Dhinesh Muthiah ^8 9 10, Zoë Bichler ¹, Barbara Mickelson ¹¹, Mei Suen Kong ¹, Vanessa Shiyun Tay ¹, Zhuang Yan ¹, Jiapeng Chen ¹, Aik Seng Ng ¹², Yun Sheng Yip ¹, Marcus Ivan Gerard Vos ¹, Nicole Ashley Tan ¹³, Dao Liang Lim ¹³, Debbie Xiu En Lim ¹, Manesh Chittezhath ¹, Jadegoud Yaligar ^2 14, Sanjay Kumar Verma ², Harish Poptani ¹⁵, Xue Li Guan ¹, Sambasivam Sendhil Velan ^2 9 14, Yusuf Ali ^1 16, Liang Li ¹⁷, Nguan Soon Tan ^1 13, Walter Wahli ^1 18 19

. 2024 Sep;11(35):e2404326.

 doi: 10.1002/advs.202404326. Epub 2024 Jul 1.

• PMID: 38952069
• PMCID: PMC11425234
• DOI: 10.1002/advs.202404326

Abstract

Metabolic dysfunction-associated steatotic liver disease (MASLD) represents an impending global health challenge. Current management strategies often face setbacks, emphasizing the need for preclinical models that faithfully mimic the human disease and its comorbidities. The liver disease progression aggravation diet (LIDPAD), a diet-induced murine model, extensively characterized under thermoneutral conditions and refined diets is introduced to ensure reproducibility and minimize species differences. LIDPAD recapitulates key phenotypic, genetic, and metabolic hallmarks of human MASLD, including multiorgan communications, and disease progression within 4 to 16 weeks. These findings reveal gut-liver dysregulation as an early event and compensatory pancreatic islet hyperplasia, underscoring the gut-pancreas axis in MASLD pathogenesis. A robust computational pipeline is also detailed for transcriptomic-guided disease staging, validated against multiple harmonized human hepatic transcriptomic datasets, thereby enabling comparative studies between human and mouse models. This approach underscores the remarkable similarity of the LIDPAD model to human MASLD. The LIDPAD model fidelity to human MASLD is further confirmed by its responsiveness to dietary interventions, with improvements in metabolic profiles, liver histopathology, hepatic transcriptomes, and gut microbial diversity. These results, alongside the closely aligned changing disease-associated molecular signatures between the human MASLD and LIDPAD model, affirm the model’s relevance and potential for driving therapeutic development.

Disentangling mechanisms behind the pleiotropic effects of proximal 16p11.2 BP4-5 CNVs

Chiara Auwerx ¹, Samuel Moix ², Zoltán Kutalik ³, Alexandre Reymond ⁴

. 2024 Sep 23:S0002-9297(24)00300-8.

 doi: 10.1016/j.ajhg.2024.08.014. Online ahead of print.

• PMID: 39332408
• DOI: 10.1016/j.ajhg.2024.08.014

Free article

Abstract

Whereas 16p11.2 BP4-5 copy-number variants (CNVs) represent one of the most pleiotropic etiologies of genomic syndromes in both clinical and population cohorts, the mechanisms leading to such pleiotropy remain understudied. Identifying 73 deletion and 89 duplication carrier individuals among unrelated White British UK Biobank participants, we performed a phenome-wide association study (PheWAS) between the region’s copy number and 117 complex traits and diseases, mimicking four dosage models. Forty-six phenotypes (39%) were affected by 16p11.2 BP4-5 CNVs, with the deletion-only, mirror, U-shape, and duplication-only models being the best fit for 30, 10, 4, and 2 phenotypes, respectively, aligning with the stronger deleteriousness of the deletion. Upon individually adjusting CNV effects for either body mass index (BMI), height, or educational attainment (EA), we found that sixteen testable deletion-driven associations-primarily with cardiovascular and metabolic traits-were BMI dependent, with EA playing a more subtle role and no association depending on height. Bidirectional Mendelian randomization supported that 13 out of these 16 associations were secondary consequences of the CNV’s impact on BMI. For the 23 traits that remained significantly associated upon individual adjustment for mediators, matched-control analyses found that 10 phenotypes, including musculoskeletal traits, liver enzymes, fluid intelligence, platelet count, and pneumonia and acute kidney injury risk, remained associated under strict Bonferroni correction, with 10 additional nominally significant associations. These results paint a complex picture of 16p11.2 BP4-5’s pleiotropic pattern that involves direct effects on multiple physiological systems and indirect co-morbidities consequential to the CNV’s impact on BMI and EA, acting through trait-specific dosage mechanisms.

The pleiotropic spectrum of proximal 16p11.2 CNVs

Chiara Auwerx ¹, Zoltán Kutalik ², Alexandre Reymond ³

. 2024 Sep 23:S0002-9297(24)00301-X.

 doi: 10.1016/j.ajhg.2024.08.015. Online ahead of print.

• PMID: 39332410
• DOI: 10.1016/j.ajhg.2024.08.015

Free article

Abstract

Recurrent genomic rearrangements at 16p11.2 BP4-5 represent one of the most common causes of genomic disorders. Originally associated with increased risk for autism spectrum disorder, schizophrenia, and intellectual disability, as well as adiposity and head circumference, these CNVs have since been associated with a plethora of phenotypic alterations, albeit with high variability in expressivity and incomplete penetrance. Here, we comprehensively review the pleiotropy associated with 16p11.2 BP4-5 rearrangements to shine light on its full phenotypic spectrum. Illustrating this phenotypic heterogeneity, we expose many parallels between findings gathered from clinical versus population-based cohorts, which often point to the same physiological systems, and emphasize the role of the CNV beyond neuropsychiatric and anthropometric traits. Revealing the complex and variable clinical manifestations of this CNV is crucial for accurate diagnosis and personalized treatment strategies for carrier individuals. Furthermore, we discuss areas of research that will be key to identifying factors contributing to phenotypic heterogeneity and gaining mechanistic insights into the molecular pathways underlying observed associations, while demonstrating how diversity in affected individuals, cohorts, experimental models, and analytical approaches can catalyze discoveries.