FoxA转录因子在肝脏发育中的研究进展

FoxA蛋白是一类DNA结合区具有翼状螺旋结构的转录因子,已发现其三名成员FoxAl、FoxA2和FoxA3在哺乳动物胚胎期的器官形成、成体时期的新陈代谢和内环境稳定中起着重要作用。肝脏发育FoxA亚家族成员起着关键调控作用,在肝向命运决定中扮演“先锋因子”的角色。该文对FoxA转录因子在肝脏发育中的调控作用进行了小结,综述了近年来的最新研究成果。     

Increased gene expression of lung marker proteins in the homeobox B3-overexpressed fetal lung cell line M3E3/C3.

Homeobox (Hox)-containing factors have been shown to play regulatory roles on lung development. Although HoxB3 gene expression is detected in the prenatal lung during development, its function has not been clarified precisely. We constructed an expression vector of a hamster HoxB3 coding region, which was cloned from hamster fetal lung cell line M3E3/C3. Sixteen-base deletion was found in the hamster HoxB3 coding sequence when compared with the mouse sequence. Under conditions of differentiation, cells transfected transiently with HoxB3 augmented the retinol-induced gene expression of Clara cell-specific secretory protein, whereas the cells showed reduced expression of surfactant-associated protein C. These alterations were attenuated by the transfection with HoxB3 antisense nucleotide. The results show that the cells with overexpressed HoxB3 were reinforced to have characteristics of Clara cells but did not have the characteristics of alveolar type II cells, and that HoxB3 played a stimulatory role on Clara cell differentiation in M3E3/C3 cells. In addition, the expression of Clara cell-specific secretory protein and surfactant-associated protein C genes was enhanced upon transfer of cells to collagen substrate, suggesting that collagen substrate has some regulatory functions on lung cell differentiation through cell adhesion.     

Methylation of HoxA5 and HoxB5 and its relevance to expression during mouse development

Expression and function of homeobox genes (Hox genes) in development have been subject to extensive study in a variety of organisms including mammals, however practically nothing is known regarding the methylation patterns of these genes. Here we describe the methylation patterns of HoxA5 and HoxB5 in various tissues of fetal and adult mice and their relevance to expression. Both genes exhibit tissue specific methylation patterns that are established postnatally. This methylation appears to play a role in stabilizing the newly acquired silent state of the genes. In contrast to the postimplantation wave of de novo methylation that takes place across the mammalian genome, the methylation of the Hox genes represents a different time window for de novo methylation which might be characteristic of developmental genes. In the case of HoxA5 this postnatal de novo methylation can cover a domain of at least 25 kb that includes several genes of the HoxA cluster and the CpG islands within. Our observations suggest that the establishment of tissue specific methylation patterns of HoxA5 and HoxB5 and the relationship between these methylation patterns and activity are different from what had been known for non-developmental genes. This may reflect the specialized functions played by Hox genes in development.     

An Mll-dependent Hox program drives hematopoietic progenitor expansion

Chromosomal translocations disrupting the Mixed lineage leukemia (Mll) gene result in leukemia, with aberrant expression of some native Mll target genes (reviewed in). The Mll gene encodes a Trithorax-group chromatin regulator that is essential for the development of hematopoietic stem cells (HSCs) during embryogenesis. Like Trithorax, MLL positively regulates clustered homeodomain or Hox genes, yet the role of Hox genes collectively in the development of the mammalian hematopoietic system has been difficult to ascertain because of redundancy among Hox paralogs. Here, we show that in the absence of MLL, early hematopoietic progenitors develop despite reduced expression of HoxA, HoxB, and HoxC genes. However, these progenitors exhibit a marked reduction in their ability to generate hematopoietic colonies, a subsequent process requiring cell division and differentiation. Reactivation of a subset of Hox genes or, remarkably, reexpression of a single Hox gene in Mll-deficient progenitors rescued hematopoietic-colony frequency and growth. In contrast, expression of other MLL target genes such as Pitx2 or expression of anti-apoptotic BCL-2 failed to rescue hematopoietic-colony frequency. Furthermore, our results highlight a shared function of Hox proteins at this point in the development of the hematopoietic system.     

HoxA and HoxB cluster genes subdivide the digestive tract into morphological domains during chick development

The digestive tract exhibits region-specific morphology and cytodifferentiation along the anteroposterior axis. We analyzed the spatial expression patterns of Hox genes belonging to the HoxA and HoxB cluster (Hoxa-4 approximately a-9, Hoxb-5 approximately b-9) in the developing chick digestive tract. The expression domains of these Hox genes correlated with morphological subdivision of the digestive tract along the anteroposterior axis.     

FoxA family members are crucial regulators of the hypertrophic chondrocyte differentiation program

During endochondral ossification, small, immature chondrocytes enlarge to form hypertrophic chondrocytes, which express collagen X. In this work, we demonstrate that FoxA factors are induced during chondrogenesis, bind to conserved binding sites in the collagen X enhancer, and can promote the expression of a collagen X-luciferase reporter in both chondrocytes and fibroblasts. In addition, we demonstrate by both gain- and loss-of-function analyses that FoxA factors play a crucial role in driving the expression of both endogenous collagen X and other hypertrophic chondrocyte-specific genes. Mice engineered to lack expression of both FoxA2 and FoxA3 in their chondrocytes display defects in chondrocyte hypertrophy, alkaline phosphatase expression, and mineralization in their sternebrae and, in addition, exhibit postnatal dwarfism that is coupled to significantly decreased expression of both collagen X and MMP13 in their growth plates. Our findings indicate that FoxA family members are crucial regulators of the hypertrophic chondrocyte differentiation program.