β-Globin cis-elements determine differential nuclear targeting through epigenetic modifications

نویسندگان

  • Qian Bian
  • Nimish Khanna
  • Jurgis Alvikas
  • Andrew S. Belmont
چکیده

Increasing evidence points to nuclear compartmentalization as a contributing mechanism for gene regulation, yet mechanisms for compartmentalization remain unclear. In this paper, we use autonomous targeting of bacterial artificial chromosome (BAC) transgenes to reveal cis requirements for peripheral targeting. Three peripheral targeting regions (PTRs) within an HBB BAC bias a competition between pericentric versus peripheral heterochromatin targeting toward the nuclear periphery, which correlates with increased H3K9me3 across the β-globin gene cluster and locus control region. Targeting to both heterochromatin compartments is dependent on Suv39H-mediated H3K9me3 methylation. In different chromosomal contexts, PTRs confer no targeting, targeting to pericentric heterochromatin, or targeting to the periphery. A combination of fluorescent in situ hybridization, BAC transgenesis, and knockdown experiments reveals that peripheral tethering of the endogenous HBB locus depends both on Suv39H-mediated H3K9me3 methylation over hundreds of kilobases surrounding HBB and on G9a-mediated H3K9me2 methylation over flanking sequences in an adjacent lamin-associated domain. Our results demonstrate that multiple cis-elements regulate the overall balance of specific epigenetic marks and peripheral gene targeting.

برای دانلود متن کامل این مقاله و بیش از 32 میلیون مقاله دیگر ابتدا ثبت نام کنید

ثبت نام

اگر عضو سایت هستید لطفا وارد حساب کاربری خود شوید

منابع مشابه

Persistent Fetal γ-Globin Expression in Adult Transgenic Mice following Deletion of Two Silencer Elements Located 3′ to the Human Aγ-Globin Gene

Human β-globin gene expression is regulated tightly during development and hematopoiesis. The human β-globin locus comprises five developmentally regulated genes (5′-ε-Gγ-Aγ-δ-β-3′) whose high level and stage-specific expression depends on interactions with the locus control region (LCR), consisting of five major DNaseI hypersensitive sites (Figure 1). The LCR activates β-globin gene transcript...

متن کامل

Concise Review: Epigenetic Regulation of Hematopoiesis: Biological Insights and Therapeutic Applications

Hematopoiesis is the process of blood cell formation starting from hematopoietic stem/progenitor cells (HSPCs). The understanding of regulatory networks involved in hematopoiesis and their impact on gene expression is crucial to decipher the molecular mechanisms that control hematopoietic development in physiological and pathological conditions, and to develop novel therapeutic strategies. An i...

متن کامل

Neutralizing the function of a β-globin-associated cis-regulatory DNA element using an artificial zinc finger DNA-binding domain.

Gene expression is primarily regulated by cis-regulatory DNA elements and trans-interacting proteins. Transcription factors bind in a DNA sequence-specific manner and recruit activities that modulate the association and activity of transcription complexes at specific genes. Often, transcription factors belong to families of related proteins that interact with similar DNA sequences. Furthermore,...

متن کامل

Dissecting the function of the adult β-globin downstream promoter region using an artificial zinc finger DNA-binding domain

Developmental stage-specific expression of the β-type globin genes is regulated by many cis- and trans-acting components. The adult β-globin gene contains an E-box located 60 bp downstream of the transcription start site that has been shown to bind transcription factor upstream stimulatory factor (USF) and to contribute to efficient in vitro transcription. We expressed an artificial zinc finger...

متن کامل

Tissue-specific histone modification and transcription factor binding in alpha globin gene expression.

To address the mechanism by which the human globin genes are activated during erythropoiesis, we have used a tiled microarray to analyze the pattern of transcription factor binding and associated histone modifications across the telomeric region of human chromosome 16 in primary erythroid and nonerythroid cells. This 220-kb region includes the alpha globin genes and 9 widely expressed genes fla...

متن کامل

ذخیره در منابع من


  با ذخیره ی این منبع در منابع من، دسترسی به آن را برای استفاده های بعدی آسان تر کنید

برای دانلود متن کامل این مقاله و بیش از 32 میلیون مقاله دیگر ابتدا ثبت نام کنید

ثبت نام

اگر عضو سایت هستید لطفا وارد حساب کاربری خود شوید

عنوان ژورنال:

دوره 203  شماره 

صفحات  -

تاریخ انتشار 2013