Regulation Of Tissue-specific Gene Expression Research Articles

Role of c-Maf in Chondrocyte Differentiation: A Review.

Chondrocyte differentiation in the growth plate is an important process for the longitudinal growth of endochondral bones. Sox9 and Runx2 are the most often-studied transcriptional regulators of the chondrocyte differentiation process, but the importance of additional factors is also becoming apparent. Mafs are a subfamily of the basic ZIP (bZIP) transcription factor superfamily, which act as key regulators of tissue-specific gene expression and terminal differentiation in many tissues. There is increasing evidence that c-Maf and its splicing variant Lc-Maf play a role in chondrocyte differentiation in a temporal-spatial manner. This review summarizes the functions of c-Maf in chondrocyte differentiation and discusses the possible role of c-Maf in osteoarthritis progression.

Adrenocortical development and cancer: focus on SF-1

Steroidogenic factor-1 (SF-1/Ad4-binding protein; NR5A1) is an essential regulator of tissue-specific gene expression in steroidogenic cells and of adrenogonadal development. Here, I discuss recent data in the literature showing the implication of SF-1 and the importance of its dosage not only during development but also for adrenal cortex tumorigenesis in humans and mice.

Gene Structure Induced Epigenetic Modifications of pericarp color1 Alleles of Maize Result in Tissue-Specific Mosaicism

BackgroundThe pericarp color1 (p1) gene encodes for a myb-homologous protein that regulates the biosynthesis of brick-red flavonoid pigments called phlobahpenes. The pattern of pigmentation on the pericarp and cob glumes depends upon the allelic constitution at the p1 locus. p1 alleles have unique gene structure and copy number which have been proposed to influence the epigenetic regulation of tissue-specific gene expression. For example, the presence of tandem-repeats has been correlated with the suppression of pericarp pigmentation though a mechanism associated with increased DNA methylation.Methodology/Principal FindingsHerein, we extensively characterize a p1 allele called P1-mosaic (P1-mm) that has mosaic pericarp and light pink or colorless cob glumes pigmentation. Relative to the P1-wr (white pericarp and red cob glumes), we show that the tandem repeats of P1-mm have a modified gene structure containing a reduced number of repeats. The P1-mm has reduced DNA methylation at a distal enhancer and elevated DNA methylation downstream of the transcription start site.Conclusions/SignificanceMosaic gene expression occurs in many eukaryotes. Herein we use maize p1 gene as model system to provide further insight about the mechanisms that govern expression mosaicism. We suggest that the gene structure of P1-mm is modified in some of its tandem gene repeats. It is known that repeated genes are susceptible to chromatin-mediated regulation of gene expression. We discuss how the modification to the tandem repeats of P1-mm may have disrupted the epigenetic mechanisms that stably confer tissue-specific expression.

Analysis of epigenetic alterations to chromatin during development

Each cell within a multicellular organism has distinguishable characteristics established by its unique patterns of gene expression. This individual identity is determined by the expression of genes in a time and place-dependent manner, and it is becoming increasingly clear that chromatin plays a fundamental role in the control of gene transcription in multicellular organisms. Therefore, understanding the regulation of chromatin and how the distinct identity of a cell is passed to daughter cells during development is paramount. Techniques with which to study chromatin have advanced rapidly over the past decade. Development of high throughput techniques and their proper applications has provided us essential tools to understand the regulation of epigenetic phenomena and its effect on gene expression. Understanding the changes that occur in chromatin during the course of development will not only contribute to our knowledge of normal gene expression, but will also add to our knowledge of how gene expression goes awry during disease. This review opens with an introduction to some of the key premises of epigenetic regulation of gene expression. A discussion of experimental techniques with which one can study epigenetic alterations to chromatin during development follows, emphasizing recent breakthroughs in this area. We then present examples of epigenetic mechanisms exploited in the control of developmental cell fate and regulation of tissue-specific gene expression. Finally, we discuss some of the frontiers and challenges in this area of research.

The Role of DNA Methylation in Regulating Tissue-Specific Gene Expression During Gametogenesis.John R. McCarrey, Ph.D.

In addition to regulating processes such as genomic imprinting and X-chromosome inactivation, abundant evidence suggests that DNA methylation also contributes to regulation of tissue-specific gene expression in both germ cells and somatic cells. In mammals, the autosomal Pgk2 gene is actively transcribed in meiotic spermatocytes and postmeiotic spermatids where it is hypomethylated in the promoter region, while it is repressed in all somatic tissues wherein the Pgk2 promoter is hypermethylated. In the spermatogenic cell lineage, a domain of demethylation develops over the Pgk2 promoter several days before activation of transcription of this gene. Changes in histone modifications, chromatin remodeling, binding of transcriptional activators and initiation of transcription from the Pgk2 promoter all occur several days after demethylation of DNA in this region. We have investigated two primary questions regarding this demethylation event and its contribution to activation of transcription from the Pgk2 promoter - 1) how is this gene- and cell type-specific demethylation event regulated? and 2) to what extent is demethylation of DNA in the promoter region of this gene a prerequisite for subsequent events leading up to and including initiation of transcription of the Pgk2 gene? Studies conducted in transgenic mice indicate that a specific region of the core promoter of the Pgk2 gene acts to signal the gene- and cell type-specific demethylation event. Thus, transgenes carrying either the Pgk2 core promoter plus the upstream enhancer region, or the core promoter region alone, ligated to a reporter coding sequence (the prokaryotic chloramphenicol acetyltransferase [CAT] gene) show gene-, and spermatogenic cell type-specific demethylation in a pattern that mimics that shown by the endogenous mouse Pgk2 gene. This demethylation event also demonstrates developmental stage-specificity during spermatogenesis, occurring during the late fetal and early postnatal periods in type T1 and type T2 prospermatogonia. However, transgenes lacking the 5' portion of the Pgk2 core promoter including the CAAT-box fail to undergo demethylation in spermatogenic cells. In addition, transgenes carrying the entire Pgk2 core promoter but with the region encompassing the CAAT-box mutated to a different sequence, also fail to undergo demethylation, indicating a gene-specific demethylation signal resides in this region. Additional studies, still in progress, indicate that when this signal sequence is disrupted such that demethylation of the Pgk2 promoter region is precluded, subsequent initiation of transcription is also precluded. Although transgenes carrying the Pgk2 core promoter undergo normal demethylation, they fail to initiate transcription unless the upstream enhancer region is also included in the transgene construct. This indicates that demethylation alone is not sufficient to activate transcription. Interestingly, transgenes carrying both the Pgk2 enhancer and core promoter regions, but with the putative demethylation signal sequence mutated to inactivity also fail to initiate transcription. This suggests that demethylation may be a necessary prerequisite for activation of transcription from this promoter. Supported by NIH grant HD46637.

Context-dependent Function of Regulatory Elements and a Switch in Chromatin Occupancy between GATA3 and GATA2 Regulate Gata2 Transcription during Trophoblast Differentiation

GATA transcription factors are important regulators of tissue-specific gene expression during development. GATA2 and GATA3 have been implicated in the regulation of trophoblast-specific genes. However, the regulatory mechanisms of GATA2 expression in trophoblast cells are poorly understood. In this study, we demonstrate that Gata2 is transcriptionally induced during trophoblast giant cell-specific differentiation. Transcriptional induction is associated with displacement of GATA3-dependent nucleoprotein complexes by GATA2-dependent nucleoprotein complexes at two regulatory regions, the -3.9- and +9.5-kb regions, of the mouse Gata2 locus. Analyses with reporter genes showed that, in trophoblast cells, -3.9- and +9.5-kb regions function as transcriptional enhancers in GATA motif independent and dependent fashions, respectively. We also found that knockdown of GATA3 by RNA interference induces GATA2 in undifferentiated trophoblast cells. Interestingly, three other known GATA motif-dependent Gata2 regulatory elements, the -1.8-, -2.8-, and -77-kb regions, which are important to regulate Gata2 in hematopoietic cells are not occupied by GATA factors in trophoblast cells. These elements do not show any enhancer activity and also possess inaccessible chromatin structure in trophoblast cells indicating a context-dependent function. Our results indicate that GATA3 directly represses Gata2 in undifferentiated trophoblast cells, and a switch in chromatin occupancy between GATA3 and GATA2 (GATA3/GATA2 switch) induces transcription during trophoblast differentiation. We predict that this GATA3/GATA2 switch is an important mechanism for the transcriptional regulation of other trophoblast-specific genes.

PASTAA: identifying transcription factors associated with sets of co-regulated genes

Motivation: A major challenge in regulatory genomics is the identification of associations between functional categories of genes (e.g. tissues, metabolic pathways) and their regulating transcription factors (TFs). While, for a limited number of categories, the regulating TFs are already known, still for many functional categories the responsible factors remain to be elucidated.Results: We put forward a novel method (PASTAA) for detecting transcriptions factors associated with functional categories, which utilizes the prediction of binding affinities of a TF to promoters. This binding strength information is compared to the likelihood of membership of the corresponding genes in the functional category under study. Coherence between the two ranked datasets is seen as an indicator of association between a TF and the category. PASTAA is applied primarily to the determination of TFs driving tissue-specific expression. We show that PASTAA is capable of recovering many TFs acting tissue specifically and, in addition, provides novel associations so far not detected by alternative methods. The application of PASTAA to detect TFs involved in the regulation of tissue-specific gene expression revealed a remarkable number of experimentally supported associations. The validated success for various datasets implies that PASTAA can directly be applied for the detection of TFs associated with newly derived gene sets.Availability: The PASTAA source code as well as a corresponding web interface is freely available at http://trap.molgen.mpg.deContact: roider@molgen.mpg.deSupplementary information: Supplementary data are available at Bioinformatics online.

A rice promoter containing both novel positive and negative cis‐elements for regulation of green tissue‐specific gene expression in transgenic plants

The tissue-specific expression of transgenes is essential in plant breeding programmes to avoid the fitness costs caused by constitutive expression of a target gene. However, knowledge on the molecular mechanisms of tissue-specific gene expression and practicable tissue-specific promoters is limited. In this study, we identified the cis-acting elements of a tissue-specific promoter from rice, P(D54O), and tested the application of original and modified P(D54O) and its cis-elements in the regulation of gene expression. P(D54O) is a green tissue-specific promoter. Five novel tissue-specific cis-elements (LPSE1, LPSE2, LPSRE1, LPSRE2, PSE1) were characterized from P(D54O). LPSE1 activated gene expression in leaf and young panicle. LPSRE2 suppressed gene expression in leaf, root, young panicle and stem, and PSE1 suppressed gene expression in young panicle and stem. LPSRE1 and LPSE2 had dual roles in the regulation of tissue-specific gene expression; both functioned as activators in leaf, but LPSRE1 acted as a repressor in stem and LPSE2 as a repressor in young panicle and root. Transgenic rice plants carrying cry1Ac encoding Bacillus thuringiensis endotoxin, regulated by P(D54O), were resistant to leaf-folders, with no Cry1Ac protein found in endosperm or embryo. A reporter gene regulated by a series of truncated P(D54O) showed various tissue-specific expression patterns. Different fragments of P(D54O) fused with the constitutive cauliflower mosaic virus 35S promoter suppressed 35S-regulated gene expression in various tissues. P(D54O), truncated P(D54O) and the tissue-specific cis-elements provide useful tools for the regulation of tissue-specific gene expression in rice breeding programmes.

Multiple Mechanisms and Functions of Maf Transcription Factors in the Regulation of Tissue-Specific Genes

Maf family transcription factors are regulators of tissue-specific gene expression and cell-differentiation in a wide variety of tissues and are also involved in human diseases and oncogenic transformation. To establish tissue-specific expression, Maf binds to Maf-recognition elements (MAREs) in the regulatory regions of target genes, and functionally interacts with other transcription factors. For example, L-Maf and c-Maf, which are specifically expressed in developing lens cells, act synergistically with Sox proteins to induce lens-specific crystalline genes. MafA, a beta-cell-specific member of the Maf family, activates the insulin gene promoter synergistically with Pdx1 and Beta2 to establish beta-cell specific expression. Furthermore, in beta-cells, MafA activity is regulated at both the transcriptional and post-translational levels by glucose and oxidative stress. This review summarizes the functions and roles of Maf in various biological processes and recent progress in elucidating the mechanisms whereby Maf proteins regulate transcription.

Alternative splicing of human and mouse NPFF2 receptor genes: Implications to receptor expression

Alternative splicing has an important role in the tissue-specific regulation of gene expression. Here we report that similar to the human NPFF2 receptor, the mouse NPFF2 receptor is alternatively spliced. In human the presence of three alternatively spliced receptor variants were verified, whereas two NPFF2 receptor variants were identified in mouse. The alternative splicing affected the 5′ untranslated region of the mouse receptor and the variants in mouse were differently distributed. The mouse NPFF system may also have species-specific features since the NPFF2 receptor mRNA expression differs from that reported for rat.

Toward a human epigenome

Sequencing of genomes, including that of humans, has revolutionized our understanding of genome organization and accelerated the hunt for disease-causing mutations. New studies by the Human Epigenome Project (HEP) now highlight the importance and complexity of cytosine DNA methylation in tissue-specific regulation of gene expression.

Differentiation-specific action of orphan nuclear receptor NR5A1 (SF-1): transcriptional regulation in luteinizing bovine theca cells

BackgroundThe orphan nuclear receptor NR5A1 (steroidogenic factor-1, SF-1) is a master regulator of tissue-specific gene expression in reproductive and steroidogenic tissues. Two activating functions, AF-1 and AF-2, have been described to function in a cooperative manner to recruit transcriptional coactivators to the promoter regions of NR5A1-controlled genes.MethodsThe role of the NR5A1 activating functions AF-1 and AF-2 was studied in primary bovine theca cells. Bovine theca cells were infected with recombinant adenovirus vectors over-expressing wild-type NR5A1 or NR5A1 mutants, in which one of the activating functions of this orphan nuclear receptor had been impaired. Under different culture conditions, theca cell-specific transcript levels were measured by reverse transcription and real-time PCR.ResultsUnder culture conditions optimized for cell growth, transcriptional up-regulation of CYP11A1 (P450 side chain-cleavage enzyme) and INSL3 (Insulin-like factor 3, Relaxin-like factor (RLF)) was found to be dependent on the presence of NR5A1 carrying an intact AF-2. Under conditions inducing luteal differentiation of theca cells, CYP11A1 and STAR (Steroidogenic acute regulatory protein) were up-regulated by the action of luteinizing hormone (LH), whereas the differentiation-specific up-regulation of INSL3 was suppressed by LH in luteinizing theca cells. Inhibition of insulin- or IGF1- (insulin-like growth factor I) dependent signal transduction by the RAF1 kinase inhibitor GW5074 and the mitogen-activated protein kinase kinase inhibitor PD98059 resulted in the finding that RAF1 kinase inhibition was able to counteract the LH-dependent regulation of NR5A1-controlled genes, whereas inhibition of the mitogen-activated protein kinase (MAP kinase) pathway did not have any significant effect.ConclusionThe regulation of the three NR5A1-controlled genes CYPA11, STAR, and INSL3 in luteinizing theca cells apparently is not dependent on NR5A1 activating functions AF-1 or AF-2. Activation of AF-1 here even appears to have an impairing effect on NR5A1 transcriptional activity, implying that up-regulation of NR5A1-controlled genes uses a different pathway. Our results might be explained by the possible existence of an interconnection between the RAF1 kinase and the cyclic AMP-protein kinase A pathway. Such a non-classical regulatory pathway might play an important role in the control of gene expression in reproductive and steroidogenic tissues.

GATA4 and the Two Sides of Gene Expression Reprogramming

See related article, pages 837–845 During embryonic development as well as in postnatal life, cardiac cells are continuously exposed to a host of extracellular signals to which they adapt and respond by activating intracellular signaling pathways and modulating the expression of nuclear genes. In the adult heart, the most common and easily recognized response to stressful stimuli is hypertrophy of cardiomyocytes and remodeling of the entire organ.1 This reactive growth response requires de novo synthesis of contractile and structural proteins, obtained through a complex series of events culminating in gene expression reprogramming.2 GATA4 is a zinc-finger transcription factor highly expressed in cardiomyocytes at different developmental stages where it regulates the transcription of several structural and regulatory genes, including atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP), α- and β-myosin heavy chain (MHC).3 In human hearts, GATA4 has also been demonstrated to be a critical regulator of cardiac development, as shown by the association between GATA4 mutations and the presence of congenital cardiac malformations.4 The specific effects of GATA4 deletion during embryonic age have been extensively investigated in genetically modified mouse models.5–7 Mice homozygous for a GATA4 null allele6 or homozygous GATA4-deficient mice (GATA4−/−)5 die early in development because of abnormal …

Generation of a conditional allele of the B‐myb gene

B-Myb is an essential transcription factor involved in control of the cell cycle and the regulation of tissue-specific gene expression in a wide range of cell types. Loss of both alleles results in early embryonic lethality at E4.5-6.5. To address the function of B-Myb in later stages of embryogenesis and in specific adult tissues, a floxed B-myb allele (B-mybF) was generated. Cre-mediated deletion in vivo was demonstrated by breeding with a transgenic GATA-Cre mouse line. An intermediate allele produced in the creation of the floxed allele, in which the PGK-neo(R) cassette is present in intron 3 (B-myb(loxneo)), was deduced to be a weak hypomorph based on the later embryonic death of homozygotes compared to B-myb(-/-) embryos. To demonstrate the efficiency and possible consequences of B-myb inactivation, we performed conditional deletion in cultured MEFs and observed decreased growth that correlated with aberrant nuclear DNA replication.

How Does Dna Methylation Mark the Fate of Cells?

Since every cell of a multicellular organism contains the same genome, it is intriguing to understand why genetically homogenous cells are different from each other and what controls this. Several observations indicate that DNA methylation has an essential regulatory function in mammalian development, which is to establish the correct pattern of gene expression, and that DNA methylation pattern is tightly correlated with chromatin structure. Various physiological processes are controlled by specific DNA methylation patterns including genomic imprinting, inactivation of the X chromosome, regulation of tissue-specific gene expression and repression of transposons. Moreover, aberrant methylation could confer a selective advantage to cells, leading to cancerous growth. In this review we focus on the epigenetic molecular mechanisms during normal development and discuss how DNA methylation could affect the expression of genes leading to cancer transformation.

Alternative splicing of mouse transcription factors affects their DNA-binding domain architecture and is tissue specific

Splice variants of 461 transcription factor loci were analyzed using a new database of splice variants in the mouse transcriptome, MouSDB3, providing quantitative evidence that alternative splicing preferentially adds or deletes domains important to the DNA-binding function of the TFs.

Regulatory Controls for Osteoblast Growth and Differentiation: Role of Runx/Cbfa/AML Factors

Formation of skeletal elements during embryogenesis and the dynamic remodeling of bone in the adult involve an exquisite interplay of developmental cues, signaling proteins, transcription factors, and their coregulatory proteins that support differentiation of osteogenic lineage cells from the initial mesenchymal progenitor cell to the mature osteocyte in mineralized connective tissue. As regulatory factors continue to be identified, the complexity of the molecular mechanisms that control gene expression in osteoblast lineage cells and drive the osteoblast maturation process are being further appreciated. A central regulator of bone formation is the Runx2 (Cbfa1/AML3) transcription factor which fulfills its role as a master regulatory switch through unique properties for mediating the temporal activation and/or repression of cell growth and phenotypic genes as osteoblasts progress through stages of differentiation. This review examines the multifunctional roles of Runx2 during osteogenesis. Runx2 functions as a "platform protein" that interacts with a spectrum of coregulatory proteins to provide a combinatorial mechanism for integrating cell signaling pathways required for osteoblast differentiation and the tissue-specific regulation of gene expression. In a broader context, it has recently been appreciated that the Runx1 hematopoietic factor and the Runx3 gene associated with neural and gut development are also expressed in the skeleton, although at present our knowledge of their roles in bone formation is limited. Here we discuss the biological functions of Runx factors in promoting cell fate determination and lineage progression, which include (1) regulating gene activation and repression through coregulatory protein interactions and by supporting chromatin remodeling; (2) integrating ECM signaling and cues from developmental, hormonal, and signal transduction pathways by formation of complexes organized in subnuclear domains; and (3) mediating cell growth control. Last, a comprehensive understanding of Runx functions in the skeleton must consider the regulatory mechanisms that control Runx2 transcription and its functional activity through posttranslational modifications.

Regulatory Controls for Osteoblast Growth and Differentiation: Role of Runx/Cbfa/AML Factors

Formation of skeletal elements during embryogenesis and the dynamic remodeling of bone in the adult involve an exquisite interplay of developmental cues, signaling proteins, transcription factors, and their coregulatory proteins that support differentiation of osteogenic lineage cells from the initial mesenchymal progenitor cell to the mature osteocyte in mineralized connective tissue. As regulatory factors continue to be identified, the complexity of the molecular mechanisms that control gene expression in osteoblast lineage cells and drive the osteoblast maturation process are being further appreciated. A central regulator of bone formation is the Runx2 (Cbfa1/AML3) transcription factor which fulfills its role as a master regulatory switch through unique properties for mediating the temporal activation and/or repression of cell growth and phenotypic genes as osteoblasts progress through stages of differentiation. This review examines the multifunctional roles of Runx2 during osteogenesis. Runx2 functions as a "platform protein" that interacts with a spectrum of coregulatory proteins to provide a combinatorial mechanism for integrating cell signaling pathways required for osteoblast differentiation and the tissue-specific regulation of gene expression. In a broader context, it has recently been appreciated that the Runx1 hematopoietic factor and the Runx3 gene associated with neural and gut development are also expressed in the skeleton, although at present our knowledge of their roles in bone formation is limited. Here we discuss the biological functions of Runx factors in promoting cell fate determination and lineage progression, which include (1) regulating gene activation and repression through coregulatory protein interactions and by supporting chromatin remodeling; (2) integrating ECM signaling and cues from developmental, hormonal, and signal transduction pathways by formation of complexes organized in subnuclear domains; and (3) mediating cell growth control. Last, a comprehensive understanding of Runx functions in the skeleton must consider the regulatory mechanisms that control Runx2 transcription and its functional activity through posttranslational modifications.

Dimerization of SOX9 is required for chondrogenesis, but not for sex determination.

The SRY-related SOX9 gene is involved in both chondrogenesis and the early steps of mammalian sex determination. Mutations in the human SOX9 gene cause campomelic dysplasia, a severe skeletal malformation syndrome associated with male-to-female sex reversal in most, but not all, XY individuals. Here we show that SOX9 contains a dimerization domain, and binds co-operatively as a dimer in the presence of the DNA enhancer element in genes involved in chondrocyte differentiation, such as Col11a2 and Col9a2, but binds as a monomer to the regulatory region of the sex-determining gene SF1. Frameshift SOX9 mutations truncate its two activation domains, while all missense mutations reported to date lie in the high mobility group (HMG) DNA-binding domain. We identify a missense mutation (A76E), the first outside the HMG domain, in an XY patient presenting with campomelic dysplasia but without sex reversal. This mutation disrupts the dimerization capability of SOX9, interfering with both the DNA binding and consequent transactivation of both the Col11a2 and Col9a2 enhancers. Consistent with the patient's phenotype, the A76E mutation does not affect DNA binding and activation of the SF1 enhancer. DNA-dependent cooperative dimerization could represent a novel mechanism to achieve tissue-specific regulation of gene expression by a SOX transcription factor. These results establish that SOX9 cooperative dimerization is required for chondrogenesis but not for sex determination and may explain why campomelic dysplasia need not be associated with XY sex reversal.

Regulation of oct-1 gene transcription is different in lymphoid and non-lymphoid cells

Transcription factor Oct-1 is expressed in all eukaryotic cells acting as a positive or negative regulator of gene transcription and DNA replication. Being a ubiquitous nuclear protein, Oct-1 also takes part in the regulation of tissue-specific gene expression. In this paper, we have found that human oct-1 gene is regulated by two promoters, located in OTF-1 locus upstream of 1U and 1L exons, respectively. The DNA region preceding U exon has a pattern typical of the constitutive gene promoters. The 5′-region upstream of 1L–exon is AT-rich, contains no TATA box, but has two octamer sequences targeted by Oct-1 and Oct-2 proteins. Analysis of promoter activity is carried out by transfection of recombinant plasmids in non-lymphoid HEK293 and lymphoid Raji cells. In non-lymphoid cells, efficiency of transcription from the 1U promoter several times exceeded that from the 1L promoter. The 1U promoter activity is little increased in the presence of an external enhancer. A different expression pattern was observed if the same constructs were transfected into lymphoid Raji cells. In this case, the level of transcription from the 1L promoter (the L–2 fragment, containing a proximal octamer site) in the presence of the enhancer was significantly higher than that of any fragments containing 1U promoter. It was shown that distal regions of both 1U and 1L were capable of silencing activity. In Raji cells, the enhancer completely overcomes the activity of U silencer, but only partly overcomes that of L silencer. Our data on tissue-specific features of 1L promoter and interaction of both oct-1 promoters with enhancer and silencers in different cell types point to a fine tissue-specific regulation of the oct-1 gene expression, especially in lymphoid cells.