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Review
. 2013 Jan;1829(1):76-83.
doi: 10.1016/j.bbagrm.2012.08.015. Epub 2012 Sep 6.

Mechanism of transcription through a nucleosome by RNA polymerase II

Olga I Kulaeva  1 , Fu-Kai Hsieh, Han-Wen Chang, Donal S Luse, Vasily M Studitsky
Affiliations
Review

Mechanism of transcription through a nucleosome by RNA polymerase II

Olga I Kulaeva et al. Biochim Biophys Acta. 2013 Jan.

Abstract

Efficient maintenance of chromatin structure during passage of RNA polymerase II (Pol II) is critical for cell survival and functioning. Moderate-level transcription of eukaryotic genes by Pol II is accompanied by nucleosome survival, extensive exchange of histones H2A/H2B and minimal exchange of histones H3/H4. Complementary in vitro studies have shown that transcription through chromatin by single Pol II complexes is uniquely coupled with nucleosome survival via formation of a small intranucleosomal DNA loop (Ø-loop) containing the transcribing enzyme. In contrast, transient displacement and exchange of all core histones are observed during intense transcription. Indeed, multiple transcribing Pol II complexes can efficiently overcome the high nucleosomal barrier and displace the entire histone octamer in vitro. Thus, various Pol II complexes can remodel chromatin to different extents. The mechanisms of nucleosome survival and displacement during transcription and the role of DNA-histone interactions and various factors during this process are discussed. This article is part of a Special Issue entitled: RNA polymerase II Transcript Elongation.

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Figures

Fig. 1
Fig. 1
Positions of nucleosome-specific pauses and strong intranucleosomal DNA-histone interactions within the nucleosome structure. A. The structure of the nucleosome core [104]. The backbone of nucleosomal DNA is shown in white and gray, the H3/H4 tetramer in purple, and the H2A/H2B dimers in green (promoter-distal D-dimer) and blue. B. The path of nucleosomal DNA. The locations of ten base pair intervals (numbered from the lower end of the nucleosome, in direction of Pol II progression (dotted arrow) along nucleosomal DNA) are indicated. Positions of strong, H2A/H2B- and H3/H4-specific DNA-histone interactions I, I′, II [32] and III (polar barrier sequence, PBS [34,35]) are indicated by green/blue and purple lanes, respectively. The regions of related strong nucleosome-specific Pol II pausing [33] are shown by blue and purple arrows.
Fig. 2
Fig. 2
Nucleosome structural changes relevant for transcription through chromatin. The nucleosome structure (1) can be perturbed due to spontaneous DNA uncoiling from the intact octamer (complex 2′ [37]), that increases the accessibility of DNA to protein binding, or by uncoiling of DNA together with the associated H2A/H2B dimer (complex 2 [43]). Formation of complexes 2 and 2′ facilitates dissociation of the H2A/H2B dimer from the nucleosome (complex 3) and dissociation of the entire octamer from DNA that occur during transcription through a nucleosome by Pol II [50].
Fig. 3
Fig. 3
Mechanism of single-round transcription through a nucleosome by Pol II in vitro (modified from [35]). Primary pathway (likely operates in vivo): as Pol II approaches a nucleosome (complex 1), (smaller arrows indicate direction of transcription), upstream nucleosomal DNA is partially uncoiled from the octamer (2). As Poll II proceeds, it encounters strong DNA-histone interactions and pauses immediately upstream of the position +49. As DNA re-coils on the octamer behind the enzyme, a transient Ø-loop is formed at position +49 (3), and Pol II displaces the promoter-distal end of nucleosomal DNA from the octamer surface (4, see Fig. 4), allowing its own further transcription. Strong sequence-specific interactions of H3/H4 histones with the PBS (polar barrier sequence) DNA region (complex 3) can prevent uncoiling of the downstream DNA and cause Pol II arrest. Otherwise Pol II continues transcription and the DNA-histone contacts upstream of the enzyme serve as an anchor to recover the nucleosome behind Pol II (5). An H2A/H2B dimer is lost during transcription (6); alternatively, 5–50% templates lose the entire octamer (complex 6′).
Fig. 4
Fig. 4
Intranucleosomal DNA Ø-loop containing transcribing Pol II. Small intranucleosomal DNA loops containing transcribing enzyme likely form several times during transcription through a nucleosome [31,35]. Formation of the such loops results in disruption of some DNA-histone interactions, formation of new histone-polymerase interactions, steric interference with the next superhelical coil of nucleosomal DNA (as in Ø-loop [35]) and displacement of ~50-bp DNA region (shown by dashed lines). Formation of small intranucleosomal, topologically closed DNA loops constrains rotation of Pol II around DNA and therefore could result in accumulation of unconstrained DNA supercoiling (positive in front and negative behind the enzyme, respectively [105]). Positive unconstrained DNA supercoiling, in turn, could induce reversible unfolding of nucleosomal DNA that remains associated with core histones [44]. Note: Pol II is not drawn to scale.
Fig. 5
Fig. 5
Mechanism of transcription through chromatin by Pol II. After initiation of transcription by Pol II, the enzyme can be paused within the first nucleosome positioned on the gene (1). After overcoming the initial nucleosomal barrier, at a low Pol II density transcription is accompanied by transient displacement/exchange of H2A/H2B dimer(s); the nucleosome structure is recovered before arrival of the next Pol II complex (2). This Pol II-specific mechanism allows survival of H3/H4 histones and their modifications on DNA during transcription. At a higher density Pol II complexes encounter hexasomes that are missing H2A/H2B dimer(s) (3). In this case an unstable intermediate with a smaller number of DNA-histone contacts is formed, resulting in eviction of the histone hexamer from DNA [62]; therefore all core histones are evicted and exchanged (3). Thus proximity of Pol II complexes to each other dictates the fate of nucleosomes on transcription.
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