HMGA Proteins in Stemness and Differentiation of Embryonic and Adult Stem Cells.

Silvia Parisi,Silvia Piscitelli,Fabiana Passaro,Tommaso Russo

doi:10.3390/ijms21010362

Silvia Parisi, Silvia Piscitelli + Show 2 more

Open Access

https://doi.org/10.3390/ijms21010362

Copy DOI

Abstract

HMGA1 and HMGA2 are chromatin architectural proteins that do not have transcriptional activity per se, but are able to modify chromatin structure by interacting with the transcriptional machinery and thus negatively or positively regulate the transcription of several genes. They have been extensively studied in cancer where they are often found to be overexpressed but their functions under physiologic conditions have still not been completely addressed. Hmga1 and Hmga2 are expressed during the early stages of mouse development, whereas they are not detectable in most adult tissues. Hmga overexpression or knockout studies in mouse have pointed to a key function in the development of the embryo and of various tissues. HMGA proteins are expressed in embryonic stem cells and in some adult stem cells and numerous experimental data have indicated that they play a fundamental role in the maintenance of stemness and in the regulation of differentiation. In this review, we discuss available experimental data on HMGA1 and HMGA2 functions in governing embryonic and adult stem cell fate. Moreover, based on the available evidence, we will aim to outline how HMGA expression is regulated in different contexts and how these two proteins contribute to the regulation of gene expression and chromatin architecture in stem cells.

Highlights

High mobility group A (HMGA) proteins are non-histone chromatin proteins
The data discussed in this review point to a crucial role of HMGA proteins in the control of the balance between self-renewal and differentiation in embryonic and adult stem cells (Table1)
These data suggest that HMGA1 fulfills the same functions in human and mouse embryonic stem cells (ESCs): its high expression in undifferentiated cells from both organisms is required for self-renewal maintenance and its downregulation is necessary for proper differentiation [8,24]

Summary

Introduction

High mobility group A (HMGA) proteins are non-histone chromatin proteins. Their classification as a high mobility group refers to their rapid electrophoretic migration, in part due to their small sizes (10–15 kDa). HMGA proteins are often expressed at very high levels in cancers [1] These include benign tumors, like for example lipomas, breast fibroadenomas, salivary gland adenomas, hamartomas, and pituitary adenomas, where in most cases, chromosome rearrangements involving the HMGA2 gene were found [1]. In the case of HMGA proteins, it was demonstrated that they accumulate in senescent cells and that their knockdown by RNAi resulted in a partial bypass of the senescence induced by oncogenic Ras [16] These data seem to conflict with the above-mentioned observation that support a role of HMGA proteins in neoplastic transformation, but indicate that the HMGA functions are context-dependent, they act as effective oncogenes, probably only when senescence-inducing mechanisms are turned off. Sci. 2020, 21, 362 the findings addressing HMGA functions in regulating stem cell behavior and outline the complex regulation of HMGA expression and how these proteins contribute to chromatin dynamics

The Phenotypes of Hmga KO and Transgenic Mice

HMGA Proteins in Adult Stem Cells

HMGA Proteins as Regulators of Chromatin Architecture and Gene Expression

Regulation of HMGA Proteins in Different Cellular Contexts

Conclusions

Findings