Combinatorial transcription factor profiles predict mature and functional human islet α and β cells

Shrestha, Shristi; Saunders, Diane; Walker, John T.; Camunas-Soler, Joan; Dai, Xiao-Qing; Haliyur, Rachana; Aramandla, Radhika; Poffenberger, Greg; Prasad, Nripesh; Bottino, Rita; Stein, Roland; Cartailler, Jean‐Philippe; Parker, Stephen C. J.; MacDonald, Patrick E.; Levy, Shawn; Powers, Alvin C.

doi:10.1101/2021.02.23.432522

Cited by 3 publications

(4 citation statements)

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“…In human α cells, variations in electrophysiologic properties, specifically capacitance and Na + currents, correlate with higher expression of α cell maturity markers and secretory genes as well as downregulation of ER stress markers (Camunas-Soler et al 2020). This observation is further supported by work from our own group, in which we showed that human α cells co-expressing the TFs MAFB and ARX had higher expression of genes involved in nutrient sensing and glucagon secretion, while α cells expressing neither TF had upregulated stress response genes (Shrestha et al 2021).…”

Section: Journal Of Endocrinologysupporting

confidence: 72%

“…Select human α cell identity markers from single-cell RNA-sequencing studies.All genes in this list are detected in human α cells from two or more independent studies(Wang et al 2016, Xin et al 2016, Enge et al 2017, Shrestha et al 2021, Gurp et al 2022, Tritschler et al 2022. Protein classes are reported via the PANTHER Classification System (www.pantherdb.org), with italicized entries inferred by the authors when no annotation was available.…”

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confidence: 99%

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The human α cell in health and disease

Pettway

Saunders

2023

Journal of Endocrinology

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In commemoration of 100 years since the discovery of glucagon, we review current knowledge about the human α cell. Alpha cells make up 30-40% of human islet endocrine cells and play a major role in regulating whole-body glucose homeostasis, largely through the direct actions of their main secretory product – glucagon – on peripheral organs. Additionally, glucagon and other secretory products of α cells, namely acetylcholine, glutamate, and GLP-1, have been shown to play an indirect role in the modulation of glucose homeostasis through autocrine and paracrine interactions within the islet. Studies of glucagon’s role as a counterregulatory hormone have revealed additional important functions of the α cell, including the regulation of multiple aspects of energy metabolism outside that of glucose. At the molecular level, human α cells are defined by expression of conserved islet-enriched transcription factors and various enriched signature genes, many of which have currently unknown cellular functions. Despite these common threads, notable heterogeneity exists amongst human α cell gene expression and function. Even greater differences are noted at the interspecies level, underscoring the importance of further study of α cell physiology in the human context. Finally, studies on α cell morphology and function in type 1 and type 2 diabetes, as well as other forms of metabolic stress, reveal a key contribution of α cell dysfunction to dysregulated glucose homeostasis in disease pathogenesis, making targeting the α cell an important focus for improving treatment.

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Section: Journal Of Endocrinologysupporting

confidence: 72%

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confidence: 99%

The human α cell in health and disease

Pettway

Saunders

2023

Journal of Endocrinology

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“…These TFs are not often co-expressed in human tissues, the exception being testes, islets, and skeletal muscle ( Supp Figure 6 ). In these unusual circumstances, MAFA and MAFB presumably act in a heterodimer complex, which has been linked with the most active human islet β cell population (Shrestha et al, 2021).…”

Section: Discussionmentioning

confidence: 99%

Defining unique structural features in the MAFA and MAFB transcription factors that controlInsulingene activity

Cha,

Tong,

Coate

et al. 2023

Preprint

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MAFA and MAFB are related basic-leucine-zipper domain containing transcription factors which have important regulatory roles in a variety of cellular contexts, including pancreatic islet hormone producing alpha and beta cells. These proteins have similar as well as distinct functional properties, and here we first used AlphaFold2, an artificial intelligence-based structural prediction program, to obtain insight into the three-dimensional organization of their non-DNA binding/dimerization sequences. This analysis was conducted on the wildtype (WT) proteins as well the pathogenic MAFASer64Phe (MAFAS64F) and MAFBSer70Ala (MAFBS70A) mutants, with structural differences revealed between MAFAWT and MAFBWT in addition to MAFAS64F and MAFAWT, but not MAFBS70A and MAFBWT. Functional analysis disclosed that the inability to properly phosphorylate at S70 in MAFBS70A, like S65 in MAFAS64F, greatly increased protein stability and enabled MAFBS70A to accelerate cellular senescence in cultured cells. Significant differences were also observed in the ability of MAFA, MAFAS64F, MAFB, and MAFBS70A to cooperatively stimulate Insulin enhancer-driven activity in the presence of other islet-enriched transcription factors. Experiments performed on protein chimeras disclosed that these properties were greatly influenced by structural differences found between the WT and mutant proteins. In general, these results revealed that AlphaFold2 predicts features essential to protein activity

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“…Postnatal β-cells are characterized by increased expression levels of cell cycle inhibitors such as Cdkn2a and a decreased expression of cell cycle activators, including FoxM1 , cyclins, and cyclin-dependent kinases ( Avrahami et al, 2015 ; Golson et al, 2015 ; Tschen et al, 2017 ). At the same time, the population of proliferating β-cells shares similarities with immature β-cells in terms of gene expression ( Nasteska et al, 2020 ; Shrestha et al, 2021 ). For example, when proliferation in the β-cells of adult transgenic mice was induced by exogenous expression of MYC proto-oncogene (Myc ), these β-cells showed a reduced expression of genes important for GSIS SLC 2 A 2, proprotein convertase subtilisin/kexin type 1 ( PCSK 1), as well as transcriptional markers of mature β-cells: Pdx 1, MafA , and Nkx 2.2 ( Puri et al, 2018 ).…”

Section: Regeneration Of the Pancreasmentioning

confidence: 99%

Development, regeneration, and physiological expansion of functional β-cells: Cellular sources and regulators

Chernysheva,

Ruchko,

Karimova

et al. 2024

Front. Cell Dev. Biol.

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Pancreatic regeneration is a complex process observed in both normal and pathological conditions. The aim of this review is to provide a comprehensive understanding of the emergence of a functionally active population of insulin-secreting β-cells in the adult pancreas. The renewal of β-cells is governed by a multifaceted interaction between cellular sources of genetic and epigenetic factors. Understanding the development and heterogeneity of β-cell populations is crucial for functional β-cell regeneration. The functional mass of pancreatic β-cells increases in situations such as pregnancy and obesity. However, the specific markers of mature β-cell populations and postnatal pancreatic progenitors capable of increasing self-reproduction in these conditions remain to be elucidated. The capacity to regenerate the β-cell population through various pathways, including the proliferation of pre-existing β-cells, β-cell neogenesis, differentiation of β-cells from a population of progenitor cells, and transdifferentiation of non-β-cells into β-cells, reveals crucial molecular mechanisms for identifying cellular sources and inducers of functional cell renewal. This provides an opportunity to identify specific cellular sources and mechanisms of regeneration, which could have clinical applications in treating various pathologies, including in vitro cell-based technologies, and deepen our understanding of regeneration in different physiological conditions.

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Combinatorial transcription factor profiles predict mature and functional human islet α and β cells

Cited by 3 publications

References 70 publications

The human α cell in health and disease

The human α cell in health and disease

Defining unique structural features in the MAFA and MAFB transcription factors that controlInsulingene activity

Development, regeneration, and physiological expansion of functional β-cells: Cellular sources and regulators

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