Modulation of nucleosomal DNA accessibility via charge-altering post-translational modifications in histone core View Full Text


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Article Info

DATE

2018-03-16

AUTHORS

Andrew T. Fenley, Ramu Anandakrishnan, Yared H. Kidane, Alexey V. Onufriev

ABSTRACT

BACKGROUND: Controlled modulation of nucleosomal DNA accessibility via post-translational modifications (PTM) is a critical component to many cellular functions. Charge-altering PTMs in the globular histone core-including acetylation, phosphorylation, crotonylation, propionylation, butyrylation, formylation, and citrullination-can alter the strong electrostatic interactions between the oppositely charged nucleosomal DNA and the histone proteins and thus modulate accessibility of the nucleosomal DNA, affecting processes that depend on access to the genetic information, such as transcription. However, direct experimental investigation of the effects of these PTMs is very difficult. Theoretical models can rationalize existing observations, suggest working hypotheses for future experiments, and provide a unifying framework for connecting PTMs with the observed effects. RESULTS: A physics-based framework is proposed that predicts the effect of charge-altering PTMs in the histone core, quantitatively for several types of lysine charge-neutralizing PTMs including acetylation, and qualitatively for all phosphorylations, on the nucleosome stability and subsequent changes in DNA accessibility, making a connection to resulting biological phenotypes. The framework takes into account multiple partially assembled states of the nucleosome at the atomic resolution. The framework is validated against experimentally known nucleosome stability changes due to the acetylation of specific lysines, and their effect on transcription. The predicted effect of charge-altering PTMs on DNA accessibility can vary dramatically, from virtually none to a strong, region-dependent increase in accessibility of the nucleosomal DNA; in some cases, e.g., H4K44, H2AK75, and H2BK57, the effect is significantly stronger than that of the extensively studied acetylation sites such H3K56, H3K115 or H3K122. Proximity to the DNA is suggestive of the strength of the PTM effect, but there are many exceptions. For the vast majority of charge-altering PTMs, the predicted increase in the DNA accessibility should be large enough to result in a measurable modulation of transcription. However, a few possible PTMs, such as acetylation of H4K77, counterintuitively decrease the DNA accessibility, suggestive of the repressed chromatin. A structural explanation for the phenomenon is provided. For the majority of charge-altering PTMs, the effect on DNA accessibility is simply additive (noncooperative), but there are exceptions, e.g., simultaneous acetylation of H4K79 and H3K122, where the combined effect is amplified. The amplification is a direct consequence of the nucleosome-DNA complex having more than two structural states. The effect of individual PTMs is classified based on changes in the accessibility of various regions throughout the nucleosomal DNA. The PTM's resulting imprint on the DNA accessibility, "PTMprint," is used to predict effects of many yet unexplored PTMs. For example, acetylation of H4K44 yields a PTMprint similar to the PTMprint of H3K56, and thus acetylation of H4K44 is predicted to lead to a wide range of strong biological effects. CONCLUSION: Charge-altering post-translational modifications in the relatively unexplored globular histone core may provide a precision mechanism for controlling accessibility to the nucleosomal DNA. More... »

PAGES

11

References to SciGraph publications

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  • 2014-03-30. Lysine 2-hydroxyisobutyrylation is a widely distributed active histone mark in NATURE CHEMICAL BIOLOGY
  • 2013-03-05. Regulation of nucleosome dynamics by histone modifications in NATURE STRUCTURAL & MOLECULAR BIOLOGY
  • 2012-05-27. Manipulating nucleosome disfavoring sequences allows fine-tune regulation of gene expression in yeast in NATURE GENETICS
  • 2003-05. The structure of DNA in the nucleosome core in NATURE
  • 1997-09. Histone acetylation in chromatin structure and transcription in NATURE
  • 2007-10-28. The nucleosome surface regulates chromatin compaction and couples it with transcriptional repression in NATURE STRUCTURAL & MOLECULAR BIOLOGY
  • Identifiers

    URI

    http://scigraph.springernature.com/pub.10.1186/s13072-018-0181-5

    DOI

    http://dx.doi.org/10.1186/s13072-018-0181-5

    DIMENSIONS

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    PUBMED

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    36 schema:description BACKGROUND: Controlled modulation of nucleosomal DNA accessibility via post-translational modifications (PTM) is a critical component to many cellular functions. Charge-altering PTMs in the globular histone core-including acetylation, phosphorylation, crotonylation, propionylation, butyrylation, formylation, and citrullination-can alter the strong electrostatic interactions between the oppositely charged nucleosomal DNA and the histone proteins and thus modulate accessibility of the nucleosomal DNA, affecting processes that depend on access to the genetic information, such as transcription. However, direct experimental investigation of the effects of these PTMs is very difficult. Theoretical models can rationalize existing observations, suggest working hypotheses for future experiments, and provide a unifying framework for connecting PTMs with the observed effects. RESULTS: A physics-based framework is proposed that predicts the effect of charge-altering PTMs in the histone core, quantitatively for several types of lysine charge-neutralizing PTMs including acetylation, and qualitatively for all phosphorylations, on the nucleosome stability and subsequent changes in DNA accessibility, making a connection to resulting biological phenotypes. The framework takes into account multiple partially assembled states of the nucleosome at the atomic resolution. The framework is validated against experimentally known nucleosome stability changes due to the acetylation of specific lysines, and their effect on transcription. The predicted effect of charge-altering PTMs on DNA accessibility can vary dramatically, from virtually none to a strong, region-dependent increase in accessibility of the nucleosomal DNA; in some cases, e.g., H4K44, H2AK75, and H2BK57, the effect is significantly stronger than that of the extensively studied acetylation sites such H3K56, H3K115 or H3K122. Proximity to the DNA is suggestive of the strength of the PTM effect, but there are many exceptions. For the vast majority of charge-altering PTMs, the predicted increase in the DNA accessibility should be large enough to result in a measurable modulation of transcription. However, a few possible PTMs, such as acetylation of H4K77, counterintuitively decrease the DNA accessibility, suggestive of the repressed chromatin. A structural explanation for the phenomenon is provided. For the majority of charge-altering PTMs, the effect on DNA accessibility is simply additive (noncooperative), but there are exceptions, e.g., simultaneous acetylation of H4K79 and H3K122, where the combined effect is amplified. The amplification is a direct consequence of the nucleosome-DNA complex having more than two structural states. The effect of individual PTMs is classified based on changes in the accessibility of various regions throughout the nucleosomal DNA. The PTM's resulting imprint on the DNA accessibility, "PTMprint," is used to predict effects of many yet unexplored PTMs. For example, acetylation of H4K44 yields a PTMprint similar to the PTMprint of H3K56, and thus acetylation of H4K44 is predicted to lead to a wide range of strong biological effects. CONCLUSION: Charge-altering post-translational modifications in the relatively unexplored globular histone core may provide a precision mechanism for controlling accessibility to the nucleosomal DNA.
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    43 schema:keywords DNA
    44 DNA accessibility
    45 H2BK57
    46 H3K115
    47 H3K122
    48 H3K56
    49 H4K44
    50 H4K44 yields
    51 H4K77
    52 H4K79
    53 PTM
    54 PTM effect
    55 PTMprint
    56 PTMprint of H3K56
    57 access
    58 accessibility
    59 account
    60 acetylation
    61 acetylation of H4K44
    62 acetylation of H4K77
    63 acetylation sites such H3K56
    64 amplification
    65 atomic resolution
    66 biological effects
    67 biological phenotypes
    68 butyrylation
    69 cases
    70 cellular functions
    71 changes
    72 charge-altering PTMs
    73 charge-neutralizing PTMs
    74 chromatin
    75 citrullination
    76 complexes
    77 components
    78 connection
    79 consequences
    80 core
    81 critical component
    82 crotonylation
    83 direct consequence
    84 direct experimental investigation
    85 effect
    86 electrostatic interactions
    87 example
    88 exception
    89 existing observations
    90 experimental investigation
    91 experiments
    92 explanation
    93 formylation
    94 framework
    95 function
    96 future experiments
    97 genetic information
    98 globular histone
    99 globular histone core
    100 histone core
    101 histone proteins
    102 histones
    103 hypothesis
    104 imprint
    105 increase
    106 individual post-translational modifications
    107 information
    108 interaction
    109 investigation
    110 lysine
    111 lysine charge-neutralizing PTMs
    112 majority
    113 measurable modulation
    114 mechanism
    115 model
    116 modification
    117 modulate accessibility
    118 modulation
    119 nucleosomal DNA
    120 nucleosomal DNA accessibility
    121 nucleosome stability
    122 nucleosome stability changes
    123 nucleosome-DNA complex
    124 nucleosomes
    125 observations
    126 observed effects
    127 phenomenon
    128 phenotype
    129 phosphorylation
    130 physics-based framework
    131 possible post-translational modifications
    132 post-translational modifications
    133 precision mechanisms
    134 process
    135 propionylation
    136 protein
    137 proximity
    138 range
    139 region
    140 region-dependent increases
    141 resolution
    142 simultaneous acetylation
    143 sites such H3K56
    144 specific lysine
    145 stability
    146 stability changes
    147 state
    148 strength
    149 strong biological effects
    150 strong electrostatic interactions
    151 structural explanation
    152 structural state
    153 subsequent changes
    154 such H3K56
    155 theoretical model
    156 transcription
    157 types
    158 unexplored PTMs
    159 unexplored globular histone core
    160 unifying framework
    161 vast majority
    162 wide range
    163 working hypothesis
    164 yield
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