class i homeobox genes, \" the rosetta stone of the cell biology \" , in the regulation of...

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Current Medicinal Chemistry, 2016, 23, 265-275 265

Class I Homeobox Genes, “The Rosetta Stone of the Cell Biology”, in the Regulation of Cardiovascular Development

Alfredo Procino*

Medical School “Federico II” of Naples, Department of Neurosciences, Reproductive, Odon-tostomatologic Sciences, Via Pansini 5 – 80131 – Naples, Italy

Abstract: Class I homeobox genes (Hox in mice and HOX in humans), encode for 39 tran-

scription factors and display a unique genomic network organization mainly involved in the

regulation of embryonic development and in the cell memory program. The HOX network

controls the aberrant epigenetic modifications involving in the cell memory program. In de-

tails, the HOX cluster plays a crucial role in the generation and evolution of several dis-

eases: congenic malformation, oncogenesis, metabolic processes and deregulation of cell

cycle. In this review, I discussed about the role of HOX gene network in the control of car-

diovascular development.

Keywords: HOX, Angiogenesis, Memory program, Rosetta stone.

1. INTRODUCTION

The cell memory is a biological process controlled

by specific gene program, able to regulate the cell fate

of the body. The “cell memory program” contains

whole information about gene functions and critical

information related to cell cycle that are transferred,

through the genome, from a cell to another cell using

cell division [1]. The memory program oversees sev-

eral aspects of the cell life: I) - the fate of a new cell;

II) the cell phenotype; III) how many cell divisions

may perform; IV) when will start apoptosis [2]. Three

gene families regulate the cell memory program: Poly-

comb family proteins are able to repress HOX genes,

keeping a compact configuration of DNA-chromatin

(heterochromatin) [3]; Trithorax proteins induce an

open configuration of DNA-chromatin (euchromatin),

allowing the HOX transcription. Finally, the HOX

network ensures the achievement of cell-specific gene

programs mainly through the transcriptional control of

the genes [4] (Fig. 1).

The Class I homeobox genes or Hox genes (Hox =

mouse and HOX = human) are a transcription factors

*Address correspondence to this author at the Medical School

“Federico II” of Naples, Department of Neurosciences, Reproduc-

tive, Odontostomatologic Sciences, Via Pansini 5 – 80131 – Naples,

Italy; Tel: +390817462080; Cell: +393473458992;

E-mail: [email protected]

family, involved in embryonal development containing

a sequence of 183 nucleotides (homeobox) encoding

for a proteic fragment of 61 aminoacids with alpha he-

lixdomain structure (homeodomain). The Homeodo-

main, binds DNA with its secondary structure at triple-

helical as biological gripper; in details the third helix

recognizes and binds a specific nucleotide sequence on

DNA. Therefore, the role of homeodomain is to pro-

mote or repress the gene expression located to down-

stream the identified sequence [5] (Fig. 2). The HOX

genes, contrariwise of Polycomb and Trithorax families

that are dispersed within the genome, present a charac-

teristic disposition and constitute the only gene net-

work, physically identifiable in the human genome and

consist of four chromosomic areas with fewer repeated

sequences of the entire genome [6]. The HOX gene

family is arranged in four chromosomal loci each con-

taining from 9 to 11 genes located on chromosomes:

7p15 HOXA, 17p21 HOXB, 12q13 HOXC and 2q31

HOXD. Besides, the genes of the HOX cluster can be

aligned, based on the sequence similarity of the ho-

meodomain, in 13 vertical paralogous group following

the overlapping of the 39 genes and based on ho-

meodomain primary structure [7].

The position of the genes within the network, identi-

fies the antero-posterior axis of the vertebrate body

from the posterior brain (hindbrain), corresponding to

the anterior limit of the HOX group cephalic genes

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266 Current Medicinal Chemistry, 2016, Vol. 23, No. 3 Alfredo Procino

(paralogous 1-4), followed by HOX thoracic group

(paralogous 5-8) and HOX lumbosacral group (paralo-

gous 9-13) in the caudal area of the body.

Fig. (2). Alpha-Helix homeodomain structure (see the text).

This characteristic is defined “colinearity” because

it is related to the arrangement of the HOX genes on

the four chromosomal loci, the anterior-posterior-

temporal genes expression and the physical body plan

[8] (Fig. 3).

Fig. (3). Schematic representation of the HOX network (see

the text).

In addition to the role of transcriptional regulators,

new crucial functions in the life of the cell have been

attributed to the HOX genes and the homeoproteins,

using their characteristic to be produced and secreted

Fig. (1). The cell memory program (see the text).

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HOX Genes and Cardiovascular Disease Current Medicinal Chemistry, 2016, Vol. 23, No. 3 267

by cells and acting on neighboring cells as true

morphogens through an internalization process [9].

Recently, the properties of homeoproteins have also

been described: i) to interact with microRNAs (miR-

NAs) and no-codingRNA (ncRNAs) in order to control

the gene expression [10, 11]; ii) select and adjust the

mRNA export from the nucleus [12]; iii) to participate

in translation processes interacting with ribosomal pro-

teins [13].

Lately, it has been shown that HOX genes are sys-

tematically involved in the hematopoietic stem cells

differentiation, regardless of the phases. In details, the

HOX genes from HOXC4 to HOXC8 and HOXA1 are

always expressed during the different phases of hema-

topoietic differentiation [14]. The data confirm the re-

cruitment of these transcription factors in the charac-

terization of hematopoietic stem cell phenotype, in the

change of immunoglobulin class and in the permutation

of the somatic cells as well as in lymphomagenesis

[15].

The simultaneous analysis of the whole HOX gene

network in different normal adult organs (kidney, colon

and lung), revealed the existence of specific pattern of

HOX genes expression for each human organ [16].

1.1. miRNAs, ncRNAs and HOX Genes

Six encoding miRNAs have been identified within

the HOX network. Three genes are located between the

HOX paralogous groups 9-10 and encoding miRNAs

196 (mir-196b, mir-196a-1 and mir-196a-2), two genes

coding for the mir-RNAs 10 (mir-10a and mir-10b)

between the paralogous group HOX 4-5 and finally the

mir-PGCEM1 to 5 'of HOXD13. Therefore, mir-196

and mir-10 show an overlapping with paralogous

groups HOX 9-10 and HOX 4-5 [17]. miRNA-196, is

involved in several neoplastic transformations such as

gastric and colorectal cancer [16]. The ncRNAs are

implicated in the epigenetic control of the interaction,

DNA-chromatin [93]. One of the most important func-

tions is given by the silencing of the X chromosome

due to ncRNA XIST through interaction with genes

Polycomb products [18]. On the locus, HOXC has been

identified as an ncRNA termed HOX transcript an-

tisense intergenic RNA (HOTAIR), which acts as a

transcriptional repressor in trans of the locus HOX D

interacting with Polycomb Responsive Element (PRE).

Closing the 3' end of the locus HOX A, between HOX

A1 and HOXA2, has been identified another ncRNA

called HOX antisense intergenic RNA myeloid 1 (HO-

TAIRM1). The ncRNA HOTAIRM1 modulates the

gene expression of HOXA locus, during myelopoiesis;

ncRNA can suppress distant domains interacting with

specific chromosomes areas [16]. Recently, it has been

identified as an lncRNA, HOXA transcript at the distal

tip (HOTTIP), transcribed from the 5’ end of the

HOXA locus that coordinates the activation of several

5’HOX A genes in vivo [19]. HOTTIP is expressed by

the development to adulthood in lumbo-sacral anatomi-

cal locations. Depletion of HOTTIP in mice induces

defects resembling HOXA11 and HOXA13 inactiva-

tion, suggesting the in vivo control of lumbosacral

HOX genes by HOTTIP [19, 20]. Finally, the molecu-

lar interactions described inside the network, support

the concept of the molecular software able to regulate

cell identity and cell-cell communication [16] (Fig. 4).

Therefore, ncRNAs are able to act on chromosomal

domains and control the expression of genes far from

each other. Moreover, ncRNA plays a crucial role in

the achievement of processes such as development,

diseases and regenerative medicine mainly by means of

smart regulation of gene expression.

1.2. Role of HOX Genes in Human Disease

Several studies have demonstrated the involvement

of homeobox genes and HOX genes in many human

diseases, from cancer to pathophysiological processes

against human organs (diabetes, cancer). A mutation in

the HOXD13 sequence, leads to synpolydactyly, a rare

hereditary disease characterized by supernumerary fin-

gers and webbed hands. The mutation, results in the

synthesis of the corresponding homeoprotein with the

expansion of alanine at the amino-terminal domain

[21]. Moreover, deregulation of HOXA13 gene, pro-

vokes a syndrome that determines malformation in the

hands, foot, uro-genital structure and goes under the

name of “hand-foot-genital syndrome” (HFG) [22].

These mutations confirm the crucial role of HOX genes

in determining the body structures and controlling of

the cell growth [23]. Mutations and/or deregulation of

HOX genes have been described in several structural

congenital alterations and associated with different

human diseases, including oncogenesis [24]. The nor-

mal development and neoplastic transformation are

characterised by similar biological events concerning

cell growth, cell proliferation, cell differentiation, cell

communication and apoptotic pathway. Changes in

specific steps of these processes, due to deregulation of

genes usually implicated in the control of cell division

and cell migration during embryonic development, lead

to the acquisition of cancer cells phenotypes [25]. Sev-

eral differences in the HOX genes expression exist be-

tween normal and neoplastic tissue, but the functional

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relationship with the cancer phenotype is not com-

pletely understood. The HOX genes expression and

malignant transformation, have been studied based on

the hypothesis that HOX genes, expressed during em-

bryonal development, can be re-expressed in neoplastic

tissue. Therefore, homeobox genes appear to regulate

normal development and normal and abnormal cell

proliferation [26]. The role of HOX network in the hu-

man leukaemia, and other neoplasia, is currently stud-

ied. Deregulation of HOX genes leads to different

forms of leukemias: myeloid leukemias (AML) and

acute lymphoid leukemias (ALL). Homeobox genes are

able to induce translocation and fusion in hematologic

neoplasia. The translocation of t (7;11) (p15, p15) in

acute myeloid leukemias, is determined by a fusion of

HOXA9 protein with amino terminus region NUP98.

The HOXA locus is always expressed in T-cells acute

lymphocytic leukemias; moreover, HOXA cluster is

upregulated in mixed-lineage leukaemia (MLL), sug-

gesting that HOXA locus is highly involved in these

leukemias, whereas HOXA9, HOXA10, HOXB3,

HOXB6 and HOX B8, are able to induce leukemias

latency. Furthermore, the co-upregulation of genes

plays a crucial role in the progression of leukaemia;

Meis homeobox-1 (MEIS-1) is an interactor of many

HOX genes, mainly with HOXB4 and HOXA9, induc-

ing Myeloid leukemia. Finally, alteration of HOX gene

network is crucial in several leukemic pathologies [24].

The influence of sex hormones on the HOX genes

expression, plays a key role in the mammary gland and

ovarian cancer; the mammary gland development, dur-

ing pregnancy, is under control of HOXA9, HOXB9,

HOXD9 [27]. On the other hand, high concentrations

of steroid hormones during pregnancy are able to

downregulate HOXC6 gene expression [28]; while, the

HOXA10 and HOXA11 genes expression increase dur-

ing the menstrual time, owing to high concentrations of

estrogen and progesterone hormones, suggesting the

involvement of these genes in endometrial develop-

ment, implantation and maintenance of pregnancy [29].

Recent evidences confirm the HOXD9 upregulation

in the synovial membrane of the rheumatoid arthritis

(RA) patients, but not in osteoarthritis or healthy indi-

viduals, suggesting that HOXD9 protein is crucial

marker in the development of this disease [30]. In con-

clusion, the homeobox genes and particularly HOX

network, control normal embryonic development, cell

differentiation and play a key role in the regulation of

critical processes for the life of the eukaryotic cell [4]

(Fig. 5). Moreover, deregulation of HOX network is

related to several diseases such as: congenital abnor-

malities [22], somatic [31], metastatic and neoplastic

[4, 16, 32-34].

1.3. HOX Genes and Cardiovascular System

Evidence demonstrates the involvement of the HOX

genes in the development of the cardiovascular system

and angiogenesis process during embryogenesis.

Moreover, the HOX network plays a crucial role in the

remodeling of blood vessels during adult life [35, 36].

The meaning of HOX genes in the structuring of the

heart has been shown for the first time in studies car-

ried out on birds [37], Drosophila and the heart of am-

phibians [38]. Subsequently, it has been deeply studied

the role of HOX genes has been in determining the an-

teroposterior polarity (A-P) in the vertebrates embry-

onic cardiac tube. The correct polarity during embry-

onic development of the cardiac tube in vertebrates, is

Fig. (4). Position of miRNA and ncRNA within network (see the text).

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crucial for the proper morphogenesis of the mature

heart. The Hox genes located in the anterior region of

the network (Hoxd3, Hoxa4, and Hoxd4) are upregu-

lated during the early stages of heart development in

chicken embryos. Moreover, Hoxd3 is overexpressed

in the region designed to the embryonic heart develop-

ment, before forming of the cardiac tube [39,40]. Re-

cently, it has identified single mutations have been

identified in HOXA1 sequence, crucial in the determi-

nation of severe cardiovascular malformations. Mice

knock out for Hoxa1, show defects as interrupted aortic

arch, aberrant subclavian artery and Tetralogy of Fal-

lot. Hoxa1 is crucial for the arrangement of the great

arteries and heart outflow tract. Moreover, at the early

stage of embryonal development, Hoxa1 is expressed

in the precursors of cardiac neural crest cells (NCCs),

present into the heart [41]. Mice knockout for Hoxa3

gene, show cardiac abnormalities and links between

circulatory and respiratory systems [36]. The HOXC5,

HOXA5 and HOXB5 expressions, induce a develop-

ment of new pharyngeal arch containing a new aortic

arch artery with regular flow. Moreover, this irregular

aortic patterning does not determine cardiac malforma-

tions [42]. HOXC9 is overexpressed, in human smooth

muscle cells and the cardiovascular system during em-

bryogenesis [43].

Fig. (5). Functions of HOX genes in the human cells (see the

text).

1.4. HOX Genes and Angiogenesis

The HOX genes located on A, B, and D locus, are

mostly expressed in endothelial cells [34] and play a

crucial role in the angiogenic phenotype acquisition

[44]. The HOX genes, through transcriptional regula-

tion of adhesion molecules and matrix proteins are able

to mediate functional changes or morphological ar-

rangement of the endothelial cells [44-46]. Recently,

the involvement of HOXA9 gene has been demon-

strated in endothelial cell migration and in vitro angio-

genesis; the HOXA9 can also regulate ephrinB4

(EphB4) gene transcription, one of the most determi-

nant genes involved in the control of human angio-

genesis. The overexpression of EphB4 gene, induces an

increase of endothelial cell migration and promoting

the development of new vessels. The HOXA9 silenc-

ing, determines down regulation of EphB4 gene, con-

sequently decreases the endothelial cells migration and

the formation of new blood vessels; positive modula-

tion of EphB4 is crucial for pro-angiogenic effect of

the HOXA9 gene [47]. Moreover, the HOXA9 gene

plays a crucial role in the development of T cells, in

hematopoiesis and stem cell expansion [48-50]. The

HOXA9 protein is also able to act as transcriptional

inhibitor blocking, in the epithelial cells, the Osteopon-

tin gene expression (SPP1). The SPP1 protein is pro-

angiogenic factor, regulated by Transforming Growth

Factor-beta (TGF-β) [51] and it is also able to influ-

ence other proteins, such as integrins αvβ3 [44,52]. Fur-

ther studies have shown the involvement of HOXA9

transcription factor in hyperplastic scar tissue during

development. Particularly, the differences are related to

the regulations of Vascular Endothelial Growth Factor

(VEGF) gene and Epidermal Stem Cells (ESCs) distri-

bution. The HOXA9 gene suppression, determines

VEGF gene silencing in ESCs. Therefore, homeobox-

A9 regulates the expression of VEGF in ESCs [53].

Recently, the involvement of Hoxa13 in extra embryo-

nal vascularization; in mice with HoxA13-/-

has been

identified in the endothelial cell (ECs) layer of umbili-

cal arteries is improperly arranged, resulting in embry-

onic lethality. The Hoxa13 protein, interacts with

EphA7 and EphA4 in ECs and the expression of both

Ephrin receptors is downregulated in the umbilical ar-

teries of mice knockout for Hoxa13 [54]. Besides, Pru-

nette ND et al have demonstrated the Hoxa3 and

Hoxc11 gene expression, using transgenic mice, in a

subset of vascular smooth muscle cells (VSMC) and

endothelial cells (ECS) located on different areas of

vascular system but corresponding to the specific ex-

pression domain of these genes [55].

The HOXB locus is highly involved in the genera-

tion of the new vessel; in effect, eight genes of the

HOXB locus are expressed in Human Umbilical Vein

Endothelial cells (HUVECs) [56]. HOXB2 is able to

block, in vitro, HUVEC proliferation [57]. HOXB5

induces transactivation of the kinase insert domain re-

cell memory program

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ceptor-1 (flt-1), the earliest marker of endothelial pre-

cursors. The HOXB5 mRNA co-localizes with flk1

protein in differentiating embryonic bodies (HBE).

Moreover, it regulates the angioblasts differentiation

and controls the new endothelial cells maturation de-

rived from mesoderm precursor [58,37]. Furthermore,

the HOXB7 factor plays a key role in the transactiva-

tion of TGF-β, VEGF, chemokine (C-X-C motif)

ligand 1 (CXCL1), Interleukin-18 (IL-8), Angio-

poietin-2 and Metalloprotinase-9 (MMP-9), all pro-

angiogenic genes [59]. The HOXB7 gene is upregu-

lated in human atherosclerotic plaques compared with

normal human arterial [60].

Several genes located on HOX3 paralogous group,

are inducer of angiogenesis. Particularly, The HOXA3

protein regulates the transcriptional control of markers

related to cell interactions such as Intracellular Adhe-

sion Molecule-1 (ICAM-1). Moreover, The HOXA3

factor is crucial in the regulation of extracellular matrix

genes such as urokinase-type plasminogen activator

receptor (��) [61]. The HOXA3 also strengthens the

angiogenesis, stimulating bone marrow-derived hema-

topoietic stem cell differentiation, towards pro-

angiogenic myeloid cells, implicated in angiogenesis

during tissue repair and in neoplastic growth [62].

Conversely, The HOXB3 promotes, in vitro, morpho-

genesis of the capillaries and angiogenesis in vivo [63],

in a different way compared to the HOXD3. Indeed,

HOXB3 protein induces the EphA1 gene expression

promoting branching out of the morphogenesis. On the

other hand, The HOXD3 transcription factor, is deter-

minant in the formation of new blood vessels, in re-

sponse to angiogenic stimulus during the neurovasco-

larization process, while HOXB3 protein takes part in

the later stages [44]. The HOXD3 gene is expressed in

the vascular endothelium of the adults, healed injuries

and in neoplastic disease in response to pro-angiogenic

factors such as TGF-β [64]. Furthermore, the HOXD3

protein appears to regulate the β3 expression, subunit

of the integrin αvβ3 and stimulates the conversion from

silent endothelium to angiogenic and invasive phase.

The quiescent endothelial cells, in contact with basal

membrane, express HOXD3, αvβ3 integrin and uPAR

genes to minimum levels. The treatment with pro-

angiogenic factors such as TGF-β, induces upregula-

tion of the HOXD3 gene and this leads to the func-

tional expression of angiogenesis promoters such as β3

integrin and uPAR [44]. Moreover, extending the

HOXD3 gene expression, is achieved an abnormal vas-

cular morphology [44]. It has been shown, that the

HOXD3 protein is selectively able to induce the gene

expression and regulates the extracellular matrix re-

modeling (EMT) during embryogenesis, exclusively in

endothelial cells [65,44]. Moreover, HOXD3 controls

the integrin α5β1 gene expression, that is a mighty regu-

lator of angiogenesis [52,66,67]. Integrin α5β1 and

HOXD3 genes are both active in the neoplastic but not

in the normal endothelium; this phenomenon suggests

that HOXD3 is a transcription factors able to regulate

α5β1 gene expression in the neoplastic endothelium. Therefore, this gene could be able to induce an activa-

tion of angiogenesis program, through the induction of

both αvβ3 and α5β1 genes expression [52]. On the other

hand, both the integrins are not able to unregulate

VEGF; moreover, none of antagonists of integrins

αvβ3 and α5β1 are able to inhibit the angiogenesis

VEGF-induced [66, 68, 69]. It has been shown that

HOXD3 gene and its direct target (integrins αvβ3 and

αvβ1), regardless of VEGF, is directed to downstream

of TGF-β and TNF-alpha, maybe the block of HOXD3

could be useful to inhibit angiogenesis in tumors re-

fractory to therapy against VEGF [52].

Other different HOX genes are able to activate or

inhibit angiogenesis; HOXA1 controls the arrangement

of mesenchymal structure, during embryonic develop-

ment. Many defects, including inappropriate vessel

formation are due to the absence of this structure.

The HOXD10 gene expression is upregulated in

quiescent endothelial cells, but the decreases in neo-

plastic microenvironment, around the angiogenic ves-

sels; furthermore, HOXD9 protein is able to suppress

angiogenesis in vivo [70], mainly through a silencing of

specific markers, required for endothelial cell migra-

tion and angiogenesis such as α3-integrin, MMP14,

uPAR and ras homolog gene family, member C (RhoC)

[71-73].

Finally, it has been shown the role of HOXB13 in

the negative control of angiogenesis by means of in-

flammation process [74]. HOXA5 inhibits angiogenesis

down-regulating angiogenic target such as kinase insert

domain receptor (VEGFR2), EPH receptor A1

(EphA1), hypoxia inducible factor 1, alpha subunit

(HIF1α) and cytochrome c oxidase subunit (COX2).

The HOXA5 protein, up-regulates the anti-angiogenic

factor thrombospondin-2 [75]. In conclusion, the HOX

genes can modulate, directly or indirectly, the migra-

tion and recruitment of endothelial cells and adjust an-

giogenesis.

1.5. The HOX Genes and Stem Cells Differentiation

Specific surface markers characterize embryonic

stem cells (ESCs): Stage-specific embryonic antigen-1

(SSEA-1), Stage-specific embryonic antigen-3 (SSEA-

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3), Stage-specific embryonic antigen-1 (SSEA-4),

TRA-1-60 and TRA-1-81 [76]. In addition, the

transcription factors Nanog, POU class 5 homeobox 1

(Oct4) and Oct3 are always expressed in the ESCs

[77,78]. The ESCs take part in crucial cellular proc-

esses: i) pluripotency; ii) take on different cell pheno-

types; iii) proliferation rate [79,80]. Class I homeobox

genes are upregulated during cellular differentiation but

how the HOX network featuring different cell lines is

still unclear [81].

Hematopoietic stem cells (HSCs), are the most used

stem cells [82]. HSCs can be isolated from bone mar-

row, peripheral blood and umbilical cord blood [83],

and are characterized by surface markers CD34, v-kit

Hardy-Zuckerman 4 feline sarcoma viral oncogene

homolog (C-KIT), TEK tyrosine kinase, endothelial

(TIE), and CD133/AC133; while CD38, LIN, and

CD45RA are always silent [84]. These stem cells dif-

ferentiate in all types of blood cell lines useful for the

regeneration of the hematopoietic lymphatic system

[85]. In details, the HOX cluster plays a key role in

hematopoiesis [86], but in particular HOXB4 transcrip-

tion factor, is crucial in the control of the transition

from hematopoietic embryonic program to hema-

topoietic adult program [81]. The HOX genes are able

to control stem cell differentiation, towards the endo-

thelial or smooth muscle phenotype. The HOXA11 and

HOXA13 proteins block the myogenic differentiation

in the vascular system, silencing myogenic differentia-

tion gene (MyoD). The Hox6 and Hox10 paralogous

groups, are always up-regulated in smooth muscle cells

(SMCs) of the athero-resistant thoracic aortic in mice

rat and pork; conversely these genes are downregulated

in SMCs athero-sensitive aortic arch. On the other

hand, the paralogous groups described upon are able to

control the human ESCs differentiation towards tho-

racic aortic arch and aortic arch phenotype [87]. Fur-

thermore, high levels of HOXB7, HOXC6 and HOXC8

proteins are expressed in the vascular wall-resident

multipotent stem-cells (VW-MPSCS), compared with

human ESCs, mature aortic smooth muscle cells and

human umbilical cord endothelial cells [88].

It has been found in mouse, the involvement of Hox

network during stem cells differentiation towards endo-

thelial cells; in details, to the third day of the differen-

tiation, a fold increase of Hoxa3 and Hoxd3 mRNA

were always detected, while the concentration was de-

creased in the following days. On the other hand, the

Hoxa5 and Hoxd10 genes were silent in the first three

days, but activated in the subsequent days [82]. There-

fore, Hoxa5 and Hoxd10 appear involved in the control

of endothelial cells phenotype, while Hoxa3 and Hoxd3

could be related to maintenance of the immature angio-

genic endothelium phenotype [82].

Stem cells isolated by bone marrow (MSCs), are

multipotent stem cells that can differentiate in several

mesenchymal tissue. In order to understand how the

HOX genes are able to lead the stem cell differentia-

tion, MSCs were transplanted in adult mouse tissue and

after few days the stem cell were able to take on the

cardiomyocytes phenotype [89-91]. Besides, HOX

network is deregulated in MSCs differentiation towards

ECs; The HOXA7 and HOXB3 genes were upregu-

lated, while HOXA3 and HOXB13 genes were silent

[92]. Moreover, VEGF-2 is an inducer of endothelia

cell precursor differentiation and was activated by

HOXB5 protein [93].

In conclusion, the analysis of the Hox genes expres-

sion in different stem cell lines and in animal models,

will provide a valuable tool for understanding the

mechanism that control the ESCs and MSCs differen-

tiation towards cardiomyocytes, in order to take advan-

tage in the field of the cardiac tissue repair.

CONCLUSION

The cardiovascular development is one of the ex-

amples of the crucial role that HOX gene network

plays in the arrangement of our body and structures.

In the last ten/fifteen year, particularly after the hu-

man genome sequencing, new discoveries have been

made about the regulation of DNA structure and the

control of gene expression. The epigenetic study re-

lated to cell memory program, control of the cell dif-

ferentiation, maintenance of the specific phenotype are

increased. Moreover, it is improved the understanding

of the risk owing to a dysregulation of human genome.

In order to continue on this way, the HOX model

would be helpful because represent a coordinate gene

network crucial for normal embryonic development,

plays a key role in the control of the cell memory pro-

gram and regulation of the cell phenotype.

The HOX genes work within the network in syn-

chrony, as musicians in an orchestra, and they are able

to regulate and control other gene programs, mainly by

means an interaction with miRNAs and ncRNAs, acti-

vating or silencing other gene; many evidences confirm

this phenomenon. In effect, a dysregulation of the net-

work is responsible for structural damage: agenesis

during embryonal development, malformation in

adults, deregulation of physiological processes and dis-

ease as neoplastic transformation. Certainly, in the next

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future will be decode the mystery of human genome,

maybe using the HOX network as “Rosetta stone of human cell biology”.

Finally, a deep study of the Class I homeobox genes

will be useful to find several answers related to the

numerous question who coming from the genome.

In memory of my father Antonio.

CONFLICT OF INTEREST

The author confirms that this article content has no

conflict of interest.

ACKNOWLEDGEMENTS

Declared none.

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Received: August 26, 2015 Revised: November 09, 2015 Accepted: December 04, 2015

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class i homeobox genes, \" the rosetta stone of the cell biology \" , in the regulation of...

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