The Haematopoietically-expressed homeobox transcription factor: roles in development, physiology and disease

Abstract

The Haematopoietically expressed homeobox transcription factor (Hhex) is a transcriptional repressor that is of fundamental importance across species, as evident by its evolutionary conservation spanning fish, amphibians, birds, mice and humans. Indeed, Hhex maintains its vital functions throughout the lifespan of the organism, beginning in the oocyte, through fundamental stages of embryogenesis in the foregut endoderm. The endodermal development driven by Hhex gives rise to endocrine organs such as the pancreas in a process which is likely linked to its role as a risk factor in diabetes and pancreatic disorders. Hhex is also required for the normal development of the bile duct and liver, the latter also importantly being the initial site of haematopoiesis. These haematopoietic origins are governed by Hhex, leading to its crucial later roles in definitive haematopoietic stem cell (HSC) self-renewal, lymphopoiesis and haematological malignancy. Hhex is also necessary for the developing forebrain and thyroid gland, with this reliance on Hhex evident in its role in endocrine disorders later in life including a potential role in Alzheimer's disease. Thus, the roles of Hhex in embryological development throughout evolution appear to be linked to its later roles in a variety of disease processes.

Keywords: AML; Hhex; T-ALL; diabetes; haematopoiesis; leakamia; transcription factor.

Figure 1

Overview of Hhex gene structure in humans. Numbers indicate amino acid position. C-Terminal (CT), eukaryotic Initiation Factor-4A (eIF4a), Homeo-Domain (HD), N-Terminal (NT), Phosphorylation Domain (PD), Promyelocytic Leukaemia protein (PML), SRY-Box Transcription Factor 13 (Sox13), Transducin-Like Enchancer/Groucho (TLE/Gro), Wingless/Integrated Signalling domain (Wnt). Gene and protein sequence information was obtained from NCBI (NM_002729.5 and NP_002720.1 respectively). Created with BioRender.com.

Figure 2

Evolutionary conservation of Hhex between divergent species. Gene amino acid sequence alignment of Hhex between species including Human, Mouse, Chicken, Xenopus and Zebrafish. Amino acid alignment highlighted in yellow. The topmost, colour-coded bar indicates the degree of conservation between species. Gene sequences were obtained from UniProt and aligned with MUSCLE alignment using SnapGene software (Version 5.2.4).

Figure 3

Established functions and interactions of Hhex in mammalian cells in various tissue and disease contexts. *Potentially other anti-apoptotic molecules are involved depending on the immunological cell type in question. Acute Myeloid Leukaemia (AML), B-cell lymphoma 2 (Bcl2), Cyclin-dependent kinase 2a (Cdkn2a), Eomesodermin (EOMES), Forkhead box e1 (Foxe1), Haematopoietic Stem Cell (HSC), (Pax8), Lim domain only 2 (Lmo2), Lysine-specific demethylase 1 (Lsd1), Polycomb Repressive Complex 2 (PRC2), Runt-related transcription factor 1 (Runx1), Sonic Hedgehog (SHH), SRY-box transcription factor 13 (Sox13), T cell Acute Lymphoblastic Leukaemia (T-ALL), Tumour Growth Factor-beta (TGF-β), Thyroid Transcription Factor-1 (TTF-1), Vascular Endothelial Growth Factor (VEGF), Wingless-Integrated/β-Catenin (Wnt/β-Cat). Created with BioRender.com.

Figure 4

Anatomical overview of Hhex in normal human physiology and disease. Acute Myeloid Leukaemia (AML), Gestational Diabetes Mellitus (GDM), Haematopoietic Stem Cell (HSC), Hepato-Cellular Carcinoma (HCC), Type II Diabetes (T2D), T cell Acute Lymphoblastic Leukaemia (T-ALL). Created with BioRender.com.