ASF1B chaperones histone 3.3 to the β-cell cycle dance

KEYWORDS:

• ASF1B
• beta-cell proliferation
• cell cycle regulation
• diabetes
• histone chaperones
• histone 3.3

This article refers to:

Histone chaperone ASF1B promotes human β-cell proliferation via recruitment of histone H3.3

A critical mass of pancreatic β-cells is required to maintain euglycemia. Insufficient β-cell mass occurs in both type 1 and type 2 diabetes (T2D). Therefore, increasing β-cell mass is an attractive avenue for cell-based therapies to restore β-cell function in diabetes. β-cells normally have a very low basal proliferation rate in lean healthy individuals.¹ Current evidence suggests that the primary mechanism for increasing β-cell mass in response to metabolic challenges such as obesity occurs predominately from the proliferation of existing β-cells and not islet neogenesis.¹ Thus, a major effort in the field is to identify factors critical to β-cell proliferation and examine their role in the expansion of β-cell mass. Previous work by the Attie group identified a network of genes across multiple tissues responsible for diabetes susceptibility, including a critical module of cell cycle genes within islets.² Within this module, anti-silencing function 1 (ASF1B) was identified among several candidate genes that showed potential to regulate cell cycle progression.

In this volume, Paul and colleagues establish a role for ASF1B in the replication of human β-cells.³ Using adenoviral overexpression of ASF1B (Ad-ASF1B), they found 460 differentially expressed genes, predominately enriched in cellular pathways involved in cell cycle regulation, mitotic progression, chromatin and histone modification by gene ontology analysis.³ Strikingly, Ad-ASF1B transduction of human islets was sufficient to cause a significant increase in β-cell proliferation without affecting other islets cell types, indicating cell-type specificity.³ By contrast, ASF1B did not affect β-cell function, as measured by glucose-stimulated insulin secretion and insulin content.³ By elegant use of a single amino acid mutation in ASF1B (V94R) the authors demonstrated that its histone binding ability is required to promote β-cell proliferation. Which histone variant is critical for these effects? Using knockdown and overexpression studies, the authors showed that histone H3.3 is required for ASF1B’s ability to regulate proliferation. Together, these experiments support the model that the transcriptional-dependent histone variant, H3.3, is required by histone chaperone ASF1B to promote S-phase progression in human β-cell proliferation.

These studies establish a new role for histone chaperones in β-cell proliferation. Furthermore, they present another example of the utility of mouse models to identify candidate factors for studies in human tissues. While ASF1B and ASF1A isoforms reveal species-specific regulation, the ASF1-histone interaction shows strong functional conservation from yeast to mouse to human in mediating enhanced proliferation. Several important future directions are suggested using the authors’ findings as a starting point. First, what are the downstream mechanisms by which ASF1B regulates proliferation? Precisely how histone chaperones and histone variants might alter β-cell proliferation remains unclear. What accounts for the specificity of ASF1B interaction with H3.3 in β-cells? And do ASF1B and H3.3 affect chromatin accessibility or epigenetic modification thereby regulating transcription?

More intriguingly, this study suggests an avenue for novel T2D therapies. The authors show that failure to upregulate ASF1B was observed in mice that were susceptible to T2D.³ This poses an important question, whether ASF1B can increase β-cell proliferation in islets of diabetic patients? If so, it would suggest that levels of ASF1B are limiting for increasing proliferation and restoring β-cell mass in diabetes. This outcome will be critical in providing the basis for identifying upstream signals that regulate ASF1B expression in β-cells. One possibility is the incretin family of hormones such as glucagon-like peptide-1 (GLP-1) and gastric inhibitory polypeptide (GIP). The role of incretins in increasing insulin secretion and β-cell proliferation is well established.⁴ The mechanism by which they act is not well understood. Both GLP-1 and GIP regulate β-cell proliferation by activation of cAMP–PKA–MEK1/2 or cAMP2–PKA–PDX1 signaling pathways. Also, they enhance association of histone H3 with cAMP–activated transcriptional regulators.⁵ Recently, Jonathan et al. showed that GIP affects β-cell function via cAMP-dependent activation of T cell-specific transcription factor-1, TCF1.⁶ Furthermore, TCF1 regulates the expression of ASF1B and affects β-cell mass.⁷ Altogether, these studies indicate the possibility that incretin signaling regulates the abundance and functional activity of ASF1B. Thus, linking incretin or other hormonal signaling to regulation of ASF1B activity would provide a new important link between the external milieu and intrinsic regulators of β-cell proliferation.

Disclosure of potential conflicts of interest

No potential conflicts of interest were disclosed.