HMGA Genes and Proteins in Development and Evolution

Abstract

HMGA (high mobility group A) (HMGA1 and HMGA2) are small non-histone proteins that can bind DNA and modify chromatin state, thus modulating the accessibility of regulatory factors to the DNA and contributing to the overall panorama of gene expression tuning. In general, they are abundantly expressed during embryogenesis, but are downregulated in the adult differentiated tissues. In the present review, we summarize some aspects of their role during development, also dealing with relevant studies that have shed light on their functioning in cell biology and with emerging possible involvement of HMGA1 and HMGA2 in evolutionary biology.

Keywords: AT hook; EMT; HMGA1; HMGA2; cell cycle; chromatin remodeling; development; differentiation; evolution; stemness.

Figure 1

Schematics of the functional organization of HMGA1 and HMGA2 proteins, showing the AT-hook domains (AT-h) and the acidic terminal tail (Ac-tail) of the proteins, as well as the residues that may be modified by acetylation (Ac), phosphorylation (Ph), or methylation (Me). Numbers indicate the position of these residues in the mature protein (initial methionine is removed post-translationally); for the HMGA1a/HMGA1b scheme they refer to the HMGA1a sequence; residues in red are only present in HMGA1a and spliced out from HMGA1b, while those in black are present both in HMGA1a and HMGA1b.

Figure 2

Graphic summary of the main sites of expression of Hmga1 and Hmga2 genes in a generalized vertebrate embryo. Colored codes resume the expression of the two genes as described in the text: ba, branchial arches; cns, central nervous system; e, eye; h, heart; i, intestine; k, kidney; li, liver; lu, lung; np, nasal placode; op, otic placode; p, pancreas; so, somites; st, stomach; t, testis.

Figure 3

Schematic representation of the HMGA1/2 pathways involved in the cell and developmental biology processes described in the text. Orange boxes include regulators of HMG1/2 proteins; green boxes include molecules regulated by HMG1/2. Blue arrows indicate positive regulation; red bars point out negative regulation. (A) adipogenesis, myogenesis, and growth; (B) stemness/self-renewal/potency; (C) EMT and EndoMT; (D) cell proliferation and senescence; (E) hematopoiesis; (F) other developmental aspects.

Figure 4

Phenotypic effects of Hmga2 depletion on Xenopus embryos. (A) Morpholino-injected stage 42 embryo show impairment of NCCs-derived skeletal elements on injected side as revealed by alcyan blue staining; (B) Neurula morphant embryo showing downregulation of snai2 expression on injected side; (C,D) A clear reduction of twist expression was observed in injected side of stage 28 tailbud embryos when compared to control side. Inj, injected side; ctrl, control side. Scale bar: (A–D) 400 μm.