HMGA2

HMGA2, or high mobility group AT-hook 2, is a small non-histone chromatin-associated protein belonging to the HMGA family. It acts as an architectural transcription factor that binds to AT-rich DNA regions through three positively charged AT-hook motifs, influencing chromatin structure and the assembly of transcriptional regulatory complexes. By bending DNA and displacing linker histone H1, HMGA2 modulates the accessibility of transcription factors to target genes and can affect multiple cellular pathways.

The HMGA2 gene is located on chromosome 12q14-15 in humans. The protein is prominently expressed during embryonic development, where it supports growth and tissue differentiation. In most adult tissues, HMGA2 expression is diminished or silenced. Experimental models show that loss of HMGA2 can result in reduced body size and adipose tissue, while its overexpression can enhance adipogenesis and certain growth-related processes.

HMGA2 expression is tightly regulated by microRNAs, particularly the let-7 family. Let-7 binding to HMGA2 mRNA suppresses translation, and LIN28 proteins can inhibit let-7, thereby increasing HMGA2 levels. Disruptions in this regulatory axis can contribute to abnormal growth and tumorigenesis.

Clinically, HMGA2 is implicated in cancer and benign tumors. Chromosomal rearrangements involving HMGA2 (for example, in pleomorphic adenomas and lipomas) often lead to HMGA2 overexpression or truncated forms that lack regulatory regions, promoting proliferation. Elevated HMGA2 expression has been observed in various malignancies and is sometimes associated with unfavorable prognosis, reflecting its role in tumor growth and invasion. HMGA2 serves as a biomarker and a subject of study in developmental biology and oncology.