Transcriptional drivers and endocrine disorders

The essential role of the endocrine system in health and well-being is universally recognized, yet the critical interplay among the more than 50 hormones that constitute this network in the human body remains to be fully defined (1). Transcriptional control is a cornerstone in coordinating endocrine function to maintain organismal homeostasis. The endocrine network must sense and respond to the diversity, context-dependence, and developmental plasticity of key transcriptional regulators to ensure temporal synchrony in the synthesis, secretion, and availability of hormones and cognate receptors. Crosstalk between transcriptional regulators and their many ‘partners’ is subject to complicated feed-forward and feed-back loops, providing additional intricacies to endocrine signaling (2). As defects at any of these levels can lead to a plethora of pathologies, a robust foundational understanding of the mechanisms governing transcription factor actions has important consequences for risk assessment, therapeutic advancement, and clinical management of endocrine disorders.

This Special Collection of four reviews and five original research articles showcases current developments on the dynamic landscape of key transcription factors associated with endocrine diseases. The body of work described herein is noteworthy for: i) the inclusion of a broad scope of endocrine pathologies (metabolic disease, cancer, female reproductive dysfunctions, Kallmann Syndrome) and cell targets (hepatocytes, pancreatic cells, uterine myometrium, ovarian granulosa cells, intestinal cells, male gametes); ii) the focus on under-studied transcription factors (KLFs, HNF) and co-factors (MEP50) and the consequences of their mutations on disease etiologies; iii) the identification of chromatin-regulatory modules (BAF, KLFs, MBD2, DNA methylation) and the mechanics of chromatin-remodeling complexes (BAF) for proper function; iv) the application of current and new technologies for discovery of pathogenic mechanisms; and v) the expansion of previously noted mechanisms for classical signaling partners (steroid hormone receptor co-activators) and pathways (AMPK phosphorylation) to support the design of target therapeutic molecules for disease management.

Disruptions in hormonal expression levels and activities underpin abnormal growth, impaired immune responses, and metabolic disorders. The studies highlighted in this collection provide important perspectives on upstream players that power appropriate hormone synthesis, secretion, and/or activity. In ovarian granulosa cells, mitochondrial DNA dysfunctions, which are induced by oxidative stress resulting in improper steroid hormone production (3), are implicated in PCOS. The uneven distribution of mutations in HNFs, leading to variants in their molecular structures, significantly influences insulin secretion in pancreatic β-cells and hence the pathogenesis of MODY (4). Moreover, the altered expression levels of distinct KLF family members in uterine myometrial cells are linked to their modified interactions with key drivers of parturition, namely progesterone receptor isoforms A/B and NFk-B, which may underpin premature or delayed labor (5). Furthermore, the comprehensive review on the dynamic roles of steroid receptor co-activators SRC-1, 2, and 3 in benign diseases of female reproductive tissues (6) supports the complex and broad scope of this multi-member family as discrete transcriptional regulators of steroid hormone-responsive genes (7) and expands their potential underpinnings of other endocrine pathologies outside of the reproductive tract.

The multi-axis regulation of endocrine signaling is further highlighted by manuscripts on BAF (8), MEP50 (9), MBD2 (10), and aberrant DNA methylation patterns (11), which provide intricate details on chromatin-level regulation and their potential roles in endocrine diseases. The BAF study reveals tissue-specific deployment of chromatin remodeling complexes that align with organ function (8), while the MEP50 study establishes this WD40 protein as a clinically relevant regulator in endocrine-related cancers (9). The SI-NET study implicates MBD2 as a potential tumor suppressor that constrains epithelial–mesenchymal transition (10). Furthermore, the identification of differentially methylated regions and spermatogenesis-related genes in Kallmann syndrome patients vs healthy controls provides insights into epigenetic mechanisms contributing to the pathogenesis of this condition (11). Together, these works expand our view of endocrine regulation beyond the transcriptome and proteome, underscoring chromatin-based processes as critical determinants underlying human disease (12).

AMPK, an enzyme that serves as a master energy sensor, has a significant role in normal metabolism, dysfunctions of which are associated with many pathologies, including diabetes and cancers. While AMPK is not a transcription factor, its direct phosphorylation of transcription factors such as CREB and its functional interactions with histones to modify the chromatin network (13, 14) place it at the center of transcriptional control of endocrine pathways. The mechanistic study on AMPK presented in this collection delineates a critical feedback loop and provides a novel targeting peptide that serves as a paradigm for addressing endocrine disorders (15).

Future research is warranted to translate the mechanisms described here into applications for specific endocrine pathologies. Detailed assessments of these and related transcription factors in both normal and diseased states will be essential for identifying optimal interventions that support societal health and promote personalized medicine.

Declaration of Interest

The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research reported.

Funding

This work did not receive any specific grant from any funding agency in the public, commercial, or not-for-profit sector.