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Gene Regulation in Endocrine Disease

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Endocrinology and Metabolism".

Deadline for manuscript submissions: closed (20 January 2025) | Viewed by 11770

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Dr. Alberto Falchetti

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Unit of Endocrinology, ASST Grande Ospedale Metropolitano Niguarda, Milan, Italy
Interests: osteoporosis; metabolic bone diseases; parathyroid diseases; multiple endocrine neoplasia; genetic diseases of bone
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Dear Colleagues,

Gene regulation, a finely tuned process, governs the activation or repression of genes, ensuring a dynamic response to internal and external cues. Within the context of endocrine physiology, this regulation is particularly crucial, dictating the synthesis and secretion of hormones that exert systemic effects on diverse tissues and organs. The dysregulation of gene expression in the endocrine system can lead to a spectrum of diseases, ranging from subtle imbalances to overt pathological states.

Endocrine diseases, sporadic and inherited or heritable, encompass a broad spectrum of conditions, including diabetes mellitus, thyroid disorders, adrenal dysfunction, neuroendocrine tumors, and disorders of the reproductive system. In each case, the perturbation of gene regulation emerges as a critical player, influencing the synthesis, release, and responsiveness of hormones. The advent of advanced genomic technologies has empowered researchers to dissect the genetic basis of these diseases, paving the way for targeted therapeutic approaches and precision medicine.

The integration of molecular genetics and endocrinology has unveiled a rich tapestry of mechanisms through which gene regulation contributes to the development and progression of endocrine disorders. From mutations in transcription factors that modulate hormone synthesis to alterations in the regulatory regions of hormone-encoding genes, the genetic landscape of endocrine diseases is becoming increasingly better understood at a molecular level. This Special Issue seeks to unravel the intricate interplay between gene regulation and endocrine diseases, offering insights into the molecular underpinnings that shape the pathophysiology of disorders within the endocrine system.

Dr. Alberto Falchetti
Guest Editor

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Keywords

gene regulation
endocrine disease
endocrinology
diabetes mellitus
thyroid disorders

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Published Papers (9 papers)

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Research

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28 pages, 12104 KiB

Open AccessArticle

The Ancestral KEAP1-NRF Pathway in Amphioxus Branchiostoma japonicum: Implications for the Evolution of Antioxidant Defense System

by Weichen Li, Xiaoqian Liang, Keyu Xiang, Hongyan Li and Yu Zhang

Int. J. Mol. Sci. 2025, 26(7), 3427; https://doi.org/10.3390/ijms26073427 - 6 Apr 2025

Viewed by 435

Abstract

The Kelch-like ECH-associated protein 1 (KEAP1)/Nuclear factor E2-related factor 2 (NRF2) pathway is a key mechanism that responds to oxidative stress and xenobiotic stimuli in vertebrates. However, knowledge of its evolutionary origins remains limited. In this study, we identify the ancestral homologues of KEAP1 and NRF (BjKEAP1 and BjNRF) in cephalochordate amphioxus (Branchiostoma japonicum). BjNRF uniquely combines the feature domains of vertebrates NRF1 and NRF2, marking it as an evolutionary intermediate. High expression levels of Bjkeap1 and Bjnrf in the gill, hepatic cecum, and intestine highlight their roles in environmental defense at key interface tissues. Functional studies reveal that BjKEAP1 regulates the cytoplasmic localization of BjNRF. Typical NRF2 activator sulforaphane (SFN) induces its nuclear translocation and significantly elevates the transcriptional expression of BjNRF and phase II detoxification enzymes. Moreover, exposure to the environmental toxin Benzo[a]pyrene (BaP) activates this stress response system. These findings bridge critical gaps in our understanding of this pathway in basal chordates and offer new insights into the evolutionary trajectory of the KEAP1-NRF system. Furthermore, this study highlights crucial implications for the conservation of amphioxus in deteriorating marine environments. Full article

(This article belongs to the Special Issue Gene Regulation in Endocrine Disease)

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15 pages, 1860 KiB

Open AccessArticle

Progerin mRNA Is Associated with Smoking and Signs of Increased Microvascular Damage in Patients with Diabetic Macular Edema

by Marc-Michael Zaruba, Reinhard Angermann, Simon Staggl, Vivek Jeyakumar, Sofia Mair, Victoria Stöckl, Julia Neyer, Thomas Maurer, Maria Ungericht, Jasmina Gavranovic-Novakovic, Axel Bauer, Claus Zehetner and Moritz Messner

Int. J. Mol. Sci. 2025, 26(5), 2099; https://doi.org/10.3390/ijms26052099 - 27 Feb 2025

Viewed by 534

Abstract

The premature aging disease Hutchinson–Gilford Syndrome (HGPS) is caused by defined mutations in the LMNA gene, resulting in the activation of a cryptic splice donor site, which leads to a defective truncated prelamin A protein called progerin. Notably, progerin expression has also been detected in non-mutated healthy individuals, and therefore, its involvement in the physiological aging process has been widely discussed. Since diabetes mellitus is associated with premature aging and increased cardiovascular mortality, we aimed to investigate the role of progerin expression in patients with diabetic retinopathy (DR). mRNA expression of progerin was analyzed in blood samples from 140 patients with DR who received anti-vascular endothelial growth factor (VEGF) therapy. Progerin mRNA levels were significantly lower in female compared to male patients (n = 42 vs. n = 98; 0.67 ± 0.19 vs. 0.89 ± 0.51, p = 0.006) and higher in patients with non-proliferative (NP)DR (n = 87 vs. n = 53; 0.9 ± 0.51 vs. 0.71 ± 0.29, p = 0.013) compared to those with proliferative (P)DR. Additionally, a positive correlation was found between progerin mRNA expression and the number of intravitreal anti-VEGF applications (n = 139, r = 0.21, p = 0.015), central macula thickness (CMT), (n = 137, r = 0.18, p = 0.036) and nicotine consumption (n = 105, r = 0.235, p = 0.002). The nuclear localization and significant upregulation of progerin mRNA and protein levels in dermal fibroblasts from HGPS donors emphasize its role in cellular aging mechanisms. Progerin mRNA levels were higher in patients with NPDR. CMT, number of intravitreal anti-VEGF therapy treatments, and cigarette consumption were positively related to progerin mRNA, suggesting an association with disease progression and premature aging. Full article

(This article belongs to the Special Issue Gene Regulation in Endocrine Disease)

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21 pages, 4132 KiB

Open AccessArticle

Red Blood Cell-Related Phenotype–Genotype Correlations in Chronic and Acute Critical Illnesses (Traumatic Brain Injury Cohort and COVID-19 Cohort)

by Darya A. Kashatnikova, Alesya S. Gracheva, Ivan V. Redkin, Vladislav E. Zakharchenko, Tatyana N. Krylova, Artem N. Kuzovlev and Lyubov E. Salnikova

Int. J. Mol. Sci. 2025, 26(3), 1239; https://doi.org/10.3390/ijms26031239 - 31 Jan 2025

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Abstract

Changes in red blood cell (RBC)-related parameters and anemia are common in both severe chronic and acute diseases. RBC-related phenotypes have a heritable component. However, it is unclear whether the contribution of genetic variability is pronounced when hematological parameters are affected by physiological stress. In this study, we analyzed RBC-related phenotypes and phenotype–genotype correlations in two exome-sequenced patient cohorts with or at a high risk for a critical illness: chronic TBI patients admitted for rehabilitation and patients with acute COVID-19. In the analysis of exome data, we focused on the cumulative effects of rare high-impact variants (qualifying variants, QVs) in specific gene sets, represented by Notch signaling pathway genes, based on the results of enrichment analysis in anemic TBI patients and three predefined gene sets for phenotypes of interest derived from GO, GWAS, and HPO resources. In both patient cohorts, anemia was associated with the cumulative effects of QVs in the GO (TBI: p = 0.0003, OR = 2.47 (1.54–4.88); COVID-19: p = 0.0004, OR = 2.12 (1.39–3.25)) and Notch pathway-derived (TBI: p = 0.0017, OR = 2.33 (1.35–4.02); COVID-19: p = 0.0012, OR =8.00 (1.79–35.74)) gene sets. In the multiple linear regression analysis, genetic variables contributed to RBC indices in patients with TBI. In COVID-19 patients, QVs in Notch pathway genes influenced RBC, HGB, and HCT levels, whereas genes from other sets influenced MCHC levels. Thus, in this exploratory study, exome data analysis yielded similar and different results in the two patient cohorts, supporting the view that genetic factors may contribute to RBC-related phenotypic performance in both severe chronic and acute health conditions. Full article

(This article belongs to the Special Issue Gene Regulation in Endocrine Disease)

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12 pages, 822 KiB

Open AccessCommunication

Defects in the Mitochondrial Genome of Dogs with Recurrent Tumours

by Krzysztof Kowal, Kaja Ziółkowska-Twarowska, Angelika Tkaczyk-Wlizło, Ludmiła Grzybowska-Szatkowska and Brygida Ślaska

Int. J. Mol. Sci. 2024, 25(24), 13414; https://doi.org/10.3390/ijms252413414 - 14 Dec 2024

Viewed by 1052

Abstract

This study presents a comprehensive analysis of mitochondrial DNA (mtDNA) variations in dogs diagnosed with primary and recurrent tumours, employing Oxford Nanopore Technologies (ONT) for sequencing. Our investigation focused on mtDNA extracted from blood and tumour tissues of three dogs, aiming to pinpoint polymorphisms, mutations, and heteroplasmy levels that could influence mitochondrial function in cancer pathogenesis. Notably, we observed the presence of mutations in the D-loop region, especially in the VNTR region, which may be crucial for mitochondrial replication, transcription, and genome stability, suggesting its potential role in cancer progression. The study is pioneering in its use of long-read sequencing to explore the mutational landscape of mtDNA in canine tumours, revealing that while the overall mutational load did not differ between primary and recurrent tumours, specific changes in m.16168A/G, m.16188G/A, and m.16298A/G are linked with tumour tissues. Interestingly, the heteroplasmy outside the D-loop region was not specific to tumour tissues and did not provoke any malignant damage in protein-coding sequences, which in turn may be a tolerant effect of the reactive oxygen species (ROS) cellular stress mechanism. Full article

(This article belongs to the Special Issue Gene Regulation in Endocrine Disease)

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17 pages, 2540 KiB

Open AccessArticle

Genomic Regions and Candidate Genes Affecting Response to Heat Stress with Newcastle Virus Infection in Commercial Layer Chicks Using Chicken 600K Single Nucleotide Polymorphism Array

by Ying Wang, Perot Saelao, Ganrea Chanthavixay, Rodrigo A. Gallardo, Anna Wolc, Janet E. Fulton, Jack M. Dekkers, Susan J. Lamont, Terra R. Kelly and Huaijun Zhou

Int. J. Mol. Sci. 2024, 25(5), 2640; https://doi.org/10.3390/ijms25052640 - 24 Feb 2024

Cited by 4 | Viewed by 2002

Abstract

Heat stress results in significant economic losses to the poultry industry. Genetics plays an important role in chickens adapting to the warm environment. Physiological parameters such as hematochemical parameters change in response to heat stress in chickens. To explore the genetics of heat stress resilience in chickens, a genome-wide association study (GWAS) was conducted using Hy-Line Brown layer chicks subjected to either high ambient temperature or combined high temperature and Newcastle disease virus infection. Hematochemical parameters were measured during three treatment phases: acute heat stress, chronic heat stress, and chronic heat stress combined with NDV infection. Significant changes in blood parameters were recorded for 11 parameters (sodium (Na⁺, potassium (K⁺), ionized calcium (iCa²⁺), glucose (Glu), pH, carbon dioxide partial pressure (PCO₂), oxygen partial pressure (PO₂), total carbon dioxide (TCO₂), bicarbonate (HCO₃), base excess (BE), and oxygen saturation (sO₂)) across the three treatments. The GWAS revealed 39 significant SNPs (p < 0.05) for seven parameters, located on Gallus gallus chromosomes (GGA) 1, 3, 4, 6, 11, and 12. The significant genomic regions were further investigated to examine if the genes within the regions were associated with the corresponding traits under heat stress. A candidate gene list including genes in the identified genomic regions that were also differentially expressed in chicken tissues under heat stress was generated. Understanding the correlation between genetic variants and resilience to heat stress is an important step towards improving heat tolerance in poultry. Full article

(This article belongs to the Special Issue Gene Regulation in Endocrine Disease)

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Review

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39 pages, 1810 KiB

Open AccessReview

The Role of the Fox Gene in Breast Cancer Progression

by Shaoxuan Pei, Dechun Zhang, Zhuohan Li, Jinkai Liu, Ziyi Li, Jianrui Chen and Zhenzhen Xie

Int. J. Mol. Sci. 2025, 26(4), 1415; https://doi.org/10.3390/ijms26041415 - 7 Feb 2025

Viewed by 1100

Abstract

Forkhead box (FOX) genes are a family of transcription factors that participate in many biological activities, from early embryogenesis to the formation of organs, and from regulation of glucose metabolism to regulation of longevity. Given the extensive influence in the multicellular process, FOX family proteins are responsible for the progression of many types of cancers, especially lung cancer, breast cancer, prostate cancer, and other cancers. Breast cancer is the most common cancer among women, and 2.3 million women were diagnosed in 2020. So, various drugs targeting the FOX signaling pathway have been developed to inhibit breast cancer progression. While the role of the FOX family gene in cancer development has not received enough attention, discovering more potential drugs targeting the FOX signaling pathway is urgently demanded. Here, we review the main members in the FOX gene family and summarize their signaling pathway, including the regulation of the FOX genes and their effects on breast cancer progression. We hope this review will emphasize the understanding of the role of the FOX gene in breast cancer and inspire the discovery of effective anti-breast cancer medicines targeting the FOX gene in the future. Full article

(This article belongs to the Special Issue Gene Regulation in Endocrine Disease)

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36 pages, 2799 KiB

Open AccessReview

Molecular Sentinels: Unveiling the Role of Sirtuins in Prostate Cancer Progression

by Surbhi Chouhan, Naoshad Muhammad, Darksha Usmani, Tabish H. Khan and Anil Kumar

Int. J. Mol. Sci. 2025, 26(1), 183; https://doi.org/10.3390/ijms26010183 - 28 Dec 2024

Cited by 3 | Viewed by 1889

Abstract

Prostate cancer (PCa) remains a critical global health challenge, with high mortality rates and significant heterogeneity, particularly in advanced stages. While early-stage PCa is often manageable with conventional treatments, metastatic PCa is notoriously resistant, highlighting an urgent need for precise biomarkers and innovative therapeutic strategies. This review focuses on the dualistic roles of sirtuins, a family of NAD+-dependent histone deacetylases, dissecting their unique contributions to tumor suppression or progression in PCa depending on the cellular context. It reveals their multifaceted impact on hallmark cancer processes, including sustaining proliferative signaling, evading growth suppressors, activating invasion and metastasis, resisting cell death, inducing angiogenesis, and enabling replicative immortality. SIRT1, for example, fosters chemoresistance and castration-resistant prostate cancer through metabolic reprogramming, immune modulation, androgen receptor signaling, and enhanced DNA repair. SIRT3 and SIRT4 suppress oncogenic pathways by regulating cancer metabolism, while SIRT2 and SIRT6 influence tumor aggressiveness and androgen receptor sensitivity, with SIRT6 promoting metastatic potential. Notably, SIRT5 oscillates between oncogenic and tumor-suppressive roles by regulating key metabolic enzymes; whereas, SIRT7 drives PCa proliferation and metabolic stress adaptation through its chromatin and nucleolar regulatory functions. Furthermore, we provide a comprehensive summary of the roles of individual sirtuins, highlighting their potential as biomarkers in PCa and exploring their therapeutic implications. By examining each of these specific mechanisms through which sirtuins impact PCa, this review underscores the potential of sirtuin modulation to address gaps in managing advanced PCa. Understanding sirtuins’ regulatory effects could redefine therapeutic approaches, promoting precision strategies that enhance treatment efficacy and improve outcomes for patients with aggressive disease. Full article

(This article belongs to the Special Issue Gene Regulation in Endocrine Disease)

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14 pages, 1222 KiB

Open AccessReview

Molecular Pathophysiology of Parathyroid Tumorigenesis—The Lesson from a Rare Disease: The “MEN1 Model”

by Alessandro Brunetti, Roberta Cosso, Fabio Vescini and Alberto Falchetti

Int. J. Mol. Sci. 2024, 25(21), 11586; https://doi.org/10.3390/ijms252111586 - 29 Oct 2024

Cited by 2 | Viewed by 1256

Abstract

Primary hyperparathyroidism represents the third most prevalent endocrine disease in the general population, consisting of an excessive secretion of parathyroid hormone from one or, more frequently, more of the parathyroid glands, leading to a dysregulation of calcium homeostasis. Schematically, its development occurs primarily by pathophysiological events with genetic mutation, at the germline and/or somatic level, that favor the neoplastic transformation of parathyroid cells and promote their aberrant proliferation, and mutations determining the shift in the PTH “set-point”, thus interfering with the normal pathways of PTH secretion and leading to a “resetting” of Ca²⁺-dependent PTH secretion or to a secretion of PTH insensitive to changes in extracellular Ca²⁺ levels. Familial syndromic and non-syndromic forms of primary hyperparathyroidism are responsible for approximately 2–5% of primary hyperparathyroidism cases and most of them are inherited forms. The history of the genetic/molecular studies of parathyroid tumorigenesis associated with multiple endocrine neoplasia type 1 syndrome (MEN1) represents an interesting model to understand genetic–epigenetic–molecular aspects underlying the pathophysiology of primary hyperparathyroidism, both in relation to syndromic and non-syndromic forms. This minireview aims to take a quick and simplified look at the MEN1-associated parathyroid tumorigenesis, focusing on the molecular underlying mechanisms. Clinical, epidemiological, and observational studies, as well as specific guidelines, molecular genetics studies, and reviews, have been considered. Only studies submitted to PubMed in the English language were included, without time constraints. Full article

(This article belongs to the Special Issue Gene Regulation in Endocrine Disease)

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17 pages, 896 KiB

Open AccessReview

Genetic Background of Medication-Related Osteonecrosis of the Jaw: Current Evidence and Future Perspectives

by Bence Bojtor, Bernadett Balla, Mihaly Vaszilko, Szofia Szentpeteri, Zsuzsanna Putz, Janos P. Kosa and Peter Lakatos

Int. J. Mol. Sci. 2024, 25(19), 10488; https://doi.org/10.3390/ijms251910488 - 29 Sep 2024

Viewed by 1830

Abstract

Medication-related osteonecrosis of the jaw (MRONJ) is a rare side effect of antiresorptive drugs that significantly hinders the quality of life of affected patients. The disease develops in the presence of a combination of factors. Important pathogenetic factors include inflammation, inhibition of bone remodeling, or genetic predisposition. Since the first description of this rare side effect in 2003, a growing body of data has suggested a possible role for genetic factors in the disease. Several genes have been suggested to play an important role in the pathogenesis of MRONJ such as SIRT1, VEGFA, and CYP2C8. With the development of molecular biology, newer methods such as miRNA and gene expression studies have been introduced in MRONJ, in addition to methods that can examine the base sequence of the DNA. Describing the complex genetic background of MRONJ can help further understand its pathophysiology as well as identify new therapeutic targets to better manage this adverse drug reaction. Full article

(This article belongs to the Special Issue Gene Regulation in Endocrine Disease)

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