Cellular analysis by in situ hybridization and immunoperoxidase of alpha-fetoprotein and albumin gene expression in rat liver during the perinatal period.

Poliard, Anne; Bernuau, Dominique; I, Tournier; Legrès, Luc; Schöevaërt, Damien; Feldmann, Gérard; Sala‐Trepat, José M.

doi:10.1083/jcb.103.3.777

Cited by 73 publications

(40 citation statements)

References 27 publications

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“…4B) could reflect DNase I cleavages be tween bound proteins. Virtually all hepatocytes express albumin mRNA (Poliard et al 1986); this, coupled with the hypersensitivity results, suggests that virtually all hepatocytes contain factors bound to the albumin pro moter. Presumably, hypersensitivity at the albumin en hancer (Pinkert et al 1987) also reflects factors bound to this liver-specific element.…”

Section: Genes and Developmentmentioning

confidence: 99%

The mouse albumin promoter and a distal upstream site are simultaneously DNase I hypersensitive in liver chromatin and bind similar liver-abundant factors in vitro.

Liu¹,

Bergman²,

Zaret³

1988

Genes Dev.

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In this paper we characterize the chromatin structure and nuclear proteins associated with different transcriptional states of the mouse serum albumin gene. We found the albumin gene to be transcribed in liver at rates 1000-fold or greater than in other tissues tested. We discovered seven DNase I hypersensitive sites encompassing the albumin gene only in liver chromatin, with strong hypersensitivity at the promoter and the enhancer, which is over 10 kb upstream. Using a gel retardation assay, we found a liver nuclear protein, or set of proteins, which binds specifically to DNA of a liver-specific hypersensitive site that maps 3.5 kb upstream, between the promoter and enhancer. Footprinting, heat insensitivity, and binding competition experiments indicate that the protein(s) have characteristics similar to a heat-stable, liver-abundant protein that binds to the albumin promoter and other enhancer and promoter sequences. Finally, we asked whether the liver-specific factors that cause DNase I hypersensitivity in vivo are present concurrently at the various sites in chromatin. We devised a simple new method to reveal that in liver, individual albumin genes are hypersensitive simultaneously at the promoter, the enhancer, and the -3.5-kb site. Thus, transcriptionally active albumin genes appear to contain tissue-abundant factors that are present at three widely spaced points in chromatin, yet at the same point in time. Similar factors binding simultaneously to at least two of these sites could create a specific structure in chromatin required for high-level albumin gene transcription.

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Section: Genes and Developmentmentioning

confidence: 99%

The mouse albumin promoter and a distal upstream site are simultaneously DNase I hypersensitive in liver chromatin and bind similar liver-abundant factors in vitro.

Liu¹,

Bergman²,

Zaret³

1988

Genes Dev.

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“…In the past, this heterogeneity has been attributed largely to gradients of metabolites that exist across the hepatic acini (12, 15) which might be expected to generate gradients of protein concentrations. However, recent examinations have revealed sharp demarcations in the distribution of some specific proteins and mRNAs so that all-or-none positional effects on gene expression seem possible (1,2,9,21). This is perhaps most dramatically illustrated by the presence in adult mouse (2) and rat (10) liver of glutamine synthetase (GS) in a single-cell layer surrounding the central vein.…”

mentioning

confidence: 99%

Positional and developmental regulation of glutamine synthetase expression in mouse liver.

Kuo¹,

Paulson²,

Darnell³

1988

Mol. Cell. Biol.

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In situ hybridization showed that all fetal hepatocytes contain glutamine synthetase (GS) mRNA but that in adult mouse liver, only a single cell layer surrounding the central veins contains GS mRNA. A shift from the fetal to the adult pattern begins within a few days of birth and is complete within 12 days of birth. Since the total GS mRNA and the transcription rate of the single GS gene are similar at birth and in adults, we conclude that there is a generalized reduction in GS transcription for most hepatocytes and a sharp rise in GS transcription for the immediate pericentral cells. This may be a case of positional regulation of specific gene transcription in apparentdy a single cell lineage.All liver parenchymal cells, or hepatocytes, are thought to be part of the same cell lineage. In the mouse, this lineage arises on day 9 or 10 of gestation when endodermal cells bud from the ventral side of the gut tube and contact mesenchymal cells from the cardiac region (13). Differentiation of hepatocytes is characterized by the coordinated expression of many secreted proteins, such as those found in serum and enzymes active in gluconeogenesis, the urea cycle, or detoxification (16). A good many of these products, serum albumin being the classic example (2, 21), appear to be produced equally by all hepatocytes in accord with the idea of there being a single cell lineage for all hepatocytes. However, it has also been recognized for many years that the concentration of some specialized hepatic proteins was not uniform throughout the liver acini (9, 16). For example, the periportal region is richer in enzymes active in gluconeogenesis (16), while the pericentral area has a higher level of enzymes active in detoxification (17,20,23,28). In the past, this heterogeneity has been attributed largely to gradients of metabolites that exist across the hepatic acini (12, 15) which might be expected to generate gradients of protein concentrations. However, recent examinations have revealed sharp demarcations in the distribution of some specific proteins and mRNAs so that all-or-none positional effects on gene expression seem possible (1,2,9,21). This is perhaps most dramatically illustrated by the presence in adult mouse (2) and rat (10) liver of glutamine synthetase (GS) in a single-cell layer surrounding the central vein. Such a sharp pattern of distribution cannot be explained simply by gradients of metabolites and therefore may represent positional regulation of gene expression within the same cell lineage.We previously showed by immunofluorescence that most mouse fetal hepatocytes stain with antiserum to GS and that not until 10 to 12 days after birth is the adult pattern of GS distribution established (2). In this paper, we used in situ hybridization, mRNA concentration studies, and transcription rate analysis to show that at least part of the regulation for this position-specific expression is at the transcriptional level. A repression of transcription in most adult hepatocytes and an increased transcription in the pericentr...

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“…Rather, reduced AFP mRNA levels are first seen in hepatocytes that reside in the perivenous regions of the liver, i.e., those cells surrounding the portal triads. AFP repression continues in a gradient-like fashion in a perivenous to pericentral direction (5,6). Thus, the last cells to express AFP before complete shut-off reside in a single layer of hepatocytes surrounding the central veins.…”

mentioning

confidence: 99%

Position-dependent activity of α-fetoprotein enhancer element III in the adult liver is due to negative regulation

Peyton

Ramesh

Spear

2000

Proc. Natl. Acad. Sci. U.S.A.

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␣-Fetoprotein (AFP) transcription is activated early in hepatogenesis, but is dramatically repressed within several weeks after birth. AFP regulation is governed by multiple elements including three enhancers termed EI, EII, and EIII. All three AFP enhancers continue to be active in the adult liver, where EI and EII exhibit high levels of activity in pericentral hepatocytes with a gradual reduction in activity in a pericentral-periportal direction. In contrast to these two enhancers, EIII activity is highly restricted to a layer of cells surrounding the central veins. To test models that could account for position-dependent EIII activity in the adult liver, we have analyzed transgenes in which AFP enhancers EII and EIII were linked together. Our results indicate that the activity of EIII is dominant over that of EII, indicating that EIII is a potent negative regulatory element in all hepatocytes except those encircling the central veins. We have localized this negative activity to a 340-bp fragment. This suggests that enhancer III may be involved in postnatal AFP repression.T he ␣-fetoprotein (AFP) gene, which encodes the major serum protein in the developing mammalian fetus, is transcribed in the yolk sac visceral endoderm, fetal liver, and, to a much lesser extent, in the fetal gut and kidney (1). AFP activation during hepatogenesis occurs as primordial hepatocytes migrate out from the developing foregut (2). The AFP gene continues to be expressed abundantly in hepatocytes during development, but is dramatically repressed postnatally (3); in the liver, this represents a nearly 10,000-fold reduction in transcription (3). The AFP gene is normally expressed at extremely low levels in the adult liver, but can be reactivated during periods of renewed cell growth such as during liver regeneration and in hepatocellular carcinomas (4).Perinatal AFP repression does not occur uniformly in all hepatocytes. Rather, reduced AFP mRNA levels are first seen in hepatocytes that reside in the perivenous regions of the liver, i.e., those cells surrounding the portal triads. AFP repression continues in a gradient-like fashion in a perivenous to pericentral direction (5, 6). Thus, the last cells to express AFP before complete shut-off reside in a single layer of hepatocytes surrounding the central veins. In addition to AFP repression, other transcriptional changes occur in the perinatal liver. In particular, the mRNAs for numerous liver enzymes become zonally expressed, i.e., synthesized exclusively in pericentral or perivenous hepatocytes (reviewed in ref. 7). For example, glutamine synthetase and ornithine aminotransferase are expressed exclusively in a narrow band of cells surrounding the central veins (8-10).Other enzymes, such as carbamoylphosphate synthetase and ornithine transcarbamylase, are expressed in a broad band of hepatocytes encircling the portal triads (10, 11). These periportal and pericentral regions of expression are nonoverlapping. The basis for this position-dependent regulation is not known, but a mathematica...

show abstract

Cellular analysis by in situ hybridization and immunoperoxidase of alpha-fetoprotein and albumin gene expression in rat liver during the perinatal period.

Cited by 73 publications

References 27 publications

The mouse albumin promoter and a distal upstream site are simultaneously DNase I hypersensitive in liver chromatin and bind similar liver-abundant factors in vitro.

The mouse albumin promoter and a distal upstream site are simultaneously DNase I hypersensitive in liver chromatin and bind similar liver-abundant factors in vitro.

Positional and developmental regulation of glutamine synthetase expression in mouse liver.

Position-dependent activity of α-fetoprotein enhancer element III in the adult liver is due to negative regulation

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