The Effects of Differentially-Expressed Homeobox Family Genes on the Prognosis and HOXC6 on Immune Microenvironment Orchestration in Colorectal Cancer.

Background: The homeobox (HOX) gene family encodes highly conserved transcription factors, that play important roles in the morphogenesis and embryonic development of vertebrates. Mammals have four similar HOX gene clusters, HOXA, HOXB, HOXC, and HOXD, which are located on chromosomes 7, 17,12 and 2 and consist of 38 genes. Some of these genes were found to be significantly related to a variety of tumors; however, it remains unknown whether abnormal expression of the HOX gene family affects prognosis and the tumor microenvironment (TME) reshaping in colorectal cancer (CRC). Therefore, we conducted this systematic exploration to provide additional information for the above questions. Methods: RNA sequencing data from The Cancer Genome Atlas (TCGA) and mRNA expression data from Gene Expression Omnibus (GEO) combined with online tumor analysis databases (UALCAN, TIMER, PrognoScan) were utilized to explore the relationship among abnormal expression of HOX family genes, prognosis and the tumor immune microenvironment in CRC. Results: 1. Differential expression and prognosis analysis: 24 genes were significantly differentially expressed in CRC compared to adjacent normal tissues, and seven upregulated genes were significantly associated with poor survival. Among these seven genes, univariate and multivariate Cox regression analysis revealed that only high expression of HOXC6 significantly contributed to poor prognosis; 2. The influence of overexpressed HOXC6 on the pathway and TME: High HOXC6 expression was significantly related to the cytokine pathway and expression of T cell attraction chemokines, the infiltration ratio of immune cells, expression of immune checkpoint markers, tumor mutation burden (TMB) scores and microsatellite instability-high (MSI-H) scores; 3. Stratified analysis based on stages: In stage IV, HOXC6 overexpression had no significant impact on TMB, MSI-H, infiltration ratio of immune cells and response prediction of immune checkpoint blockers (ICBs), which contributed to significantly poor overall survival (OS). Conclusion: Seven differentially expressed HOX family genes had significantly worse prognoses. Among them, overexpressed HOXC6 contributed the most to poor OS. High expression of HOXC6 was significantly associated with high immunogenicity in nonmetastatic CRC. Further research on HOXC6 is therefore worthwhile to provide potential alternatives in CRC immunotherapy.

Expression profiling of immature thymocytes revealed a novel homeobox gene that regulates double-negative thymocyte development.

Intrathymic development of CD4/CD8 double-negative (DN) thymocytes can be tracked by well-defined chronological subsets of thymocytes, and is an ideal target of gene expression profiling analysis to clarify the genetic basis of mature T cell production, by which differentiation of immature thymocytes is investigated in terms of gene expression profiles. In this study, we show that development of murine DN thymocytes is predominantly regulated by largely repressive rather than inductive activities of transcriptions, where lineage-promiscuous gene expression in immature thymocytes is down-regulated during their differentiation. Functional mapping of genes showing common temporal expression profiles implicates previously uncharacterized gene regulations that may be relevant to early thymocytes development. A small minority of genes is transiently expressed in the CD44(low)CD25(+) subset of DN thymocytes, from which we identified a novel homeobox gene, Duxl, whose expression is up-regulated by Runx1. Duxl promotes the transition from CD44(high)CD25(+) to CD44(low)CD25(+) in DN thymocytes, while constitutive expression of Duxl inhibits expression of TCR beta-chains and leads to impaired beta selection and greatly reduced production of CD4/CD8 double-positive thymocytes, indicating its critical roles in DN thymocyte development.

¿Qué son los genes Hox? Su importancia en la enfermedad vascular y renal / No disponible

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Down-regulation of the myeloid homeobox protein Hex is essential for normal T-cell development.

The haematopoietic homeobox gene Hex (also called Prh) is expressed in myeloid cells and B cells but not T cells. To investigate whether Hex levels might play a role in myeloid versus T-cell development, two types of transgenic mouse lines were constructed, each with ectopic expression of Hex in T cells (CD11a/Hex and Lck/Hex). Both these types of transgenic mouse had the same defects in T-cell maturation, indicating that proper T-cell development may be dependent not just on the up-regulation of lymphoid-specific transcriptional regulators but also on the co-ordinated down-regulation of myeloid-specific transcriptional regulators such as Hex. In addition, Hex over-expression significantly increased myeloid progenitor cycling, which may explain its role in retrovirally induced murine leukaemia.

Cutting edge: polycomb gene expression patterns reflect distinct B cell differentiation stages in human germinal centers.

Polycomb group (Pc-G) proteins regulate homeotic gene expression in Drosophila, mouse, and humans. Mouse Pc-G proteins are also essential for adult hematopoietic development and contribute to cell cycle regulation. We show that human Pc-G expression patterns correlate with different B cell differentiation stages and that they reflect germinal center (GC) architecture. The transition of resting mantle B cells to rapidly dividing Mib-1(Ki-67)+ follicular centroblasts coincides with loss of BMI-1 and RING1 Pc-G protein detection and appearance of ENX and EED Pc-G protein expression. By contrast, differentiation of centroblasts into centrocytes correlates with reappearance of BMI-1/RING1 and loss of ENX/EED and Mib-1 expression. The mutually exclusive expression of ENX/EED and BMI-1/RING1 reflects the differential composition of two distinct Pc-G complexes. The Pc-G expression profiles in various GC B cell differentiation stages suggest a role for Pc-G proteins in GC development.

HOXB cluster genes in activated natural killer lymphocytes: expression from 3'-->5' cluster side and proliferative function.

The expression of HOXB cluster genes (i.e., B1 through B9) was evaluated in purified IL-2/IL-1 beta-activated NK lymphocytes from normal adult peripheral blood by RNase protection and reverse transcription-PCR. In quiescent NK cells these genes are essentially not expressed. After IL-2/IL-1 beta addition, we observed a coordinate induction wave in the 3'-5' HOXB cluster direction, i.e., from B1 through B9. As notable exceptions, B8 is silent, while B9 RNA is detected starting from 6 h through day 11. Furthermore, the 3' located B2/B3/B4 are expressed earlier and at higher level than the 5' located B5/B6/B7/B8. In IL-2/IL-1 beta-activated NK cells, treatment with antisense oligonucleotides targeting B2 mRNA causes a significant inhibition of both cell proliferation and expression of activation markers (i.e., IL-2R alpha-chain and transferrin receptor). These studies provide novel evidence of the role of HOX genes in adult NK cell proliferation. Thus, 1) a coordinate activation of HOXB genes from the 3'-->5' cluster side apparently underlies IL-2/IL-1 beta-induced NK cell activation. 2) Since NK cell activation and survival induced by IL-12 and c-kit ligand, respectively, are not associated with cell proliferation of HOXB gene expression, it is apparent that HOXB gene induction is specifically associated with IL-2-induced NK cell proliferation. 3) Studies with antisense oligomer targeting HOXB2 mRNA suggest an important role for 82 in NK cell proliferation, possibly in part via the IL-2R.

Transcription factors in early T-cell development.

Characterization of the transcription control regions for most genes encoding the TCR-CD3 complex has been followed by identification of DNA-binding factors, some of which are restricted to lymphoid or T-lineage cells. The sequential expression of these factors is linked with the appearance of stage-specific T-cell markers, thus controlling the commitment of the elusive lymphoid progenitor cell and its progression along the T-lineage. Here, Hans Clevers, Mariëtte Oosterwegel and Katia Georgopoulos discuss recent progress made in the recognition of transcription factors that regulate these early events in T-cell ontogeny.

The Drosophila zfh-1 and zfh-2 genes encode novel proteins containing both zinc-finger and homeodomain motifs.

Two of the most common DNA-binding motifs found in eukaryotic transcriptional regulatory proteins are the homeodomain and the C2-H2 zinc finger. In Drosophila, homeodomain and zinc-finger proteins have been implicated in a wide variety of developmental processes. Until now, no proteins have been described in which both these DNA-binding motifs are present. We report here the isolation of genes encoding two such Drosophila proteins from a cDNA expression library. The product of the zfh-1 gene (zinc-finger homeodomain protein 1) contains one homeodomain and nine C2-H2 zinc fingers. The product of the zfh-2 gene possesses three homeodomains and sixteen C2-H2 zinc fingers. For zfh-1, antisera raised against nonoverlapping regions of the gene product all recognize a 145 kDa protein on protein immunoblots, suggesting that the different DNA-binding motifs are actually all present in the mature gene product. The novel arrangement of interspersed homeodomain and zinc-finger motifs in the primary sequences of the zfh-1 and zfh-2 gene products may signify an unusual mechanism of transcriptional regulation by these proteins.

The embryonic expression patterns of zfh-1 and zfh-2, two Drosophila genes encoding novel zinc-finger homeodomain proteins.

The zfh-1 and zfh-2 genes of D. melanogaster encode novel proteins containing both homeodomain and C2-H2 zinc-finger DNA-binding motifs. Antisera against these proteins were used to investigate their expression patterns during embryonic development. The zfh-1 gene is expressed in the mesoderm of early embryos and in a number of mesodermally-derived structures of late embryos, including the dorsal vessel, support cells of the gonads, and segment-specific arrays of adult muscle precursors. In addition, zfh-1 is expressed in the majority of identified motor neurons of the developing CNS. The mesodermal zfh-1 expression requires the products of the twist and snail genes. The zfh-2 gene displays a more limited expression pattern, largely restricted to the CNS of late embryos. Ubiquitous zfh-1 expression in transgenic flies bearing an hsp70-zfh-1 construct has specific developmental consequences, including embryonic CNS defects as well as adult eye and bristle abnormalities. The expression patterns of zfh-1 and zfh-2 suggest that both genes may be involved in Drosophila neurogenesis and that zfh-1 may have additional functions in mesoderm development.

Expression and regulation of the abd-A gene of Drosophila.

We have developed a specific polyclonal antibody that recognizes the protein products of the abdominal-A (abd-A) gene, a member of the bithorax complex of Drosophila. The normal expression domain extends from parasegments 7 to 13, in good correspondence with previous genetic and molecular results. However, while the anterior border of expression is precisely demarcated by a parasegmental boundary, the posterior border does not coincide with a lineage boundary. Within the normal domain, the expression of abd-A shows intrametameric modulation; the amount of product is higher in posterior compartments and in the most anterior cells of the anterior compartments and then gradually decreases. We have examined the effect on abd-A expression of a number of mutations, some mapping within and others outside the abd-A transcription unit. Those mapping to the transcription unit eliminate or severely reduce the amount of abd-A antigen, while those mapping outside produce an abnormal distribution of abd-A protein. Finally, we show that the abd-A gene is down-regulated in part of the Abdominal-B (Abd-B) domain, precisely in those regions where the Abd-B gene is expressed at high levels.