Modeling DNA Sequence Based cis-Regulatory Gene Networks

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Modeling DNA Sequence Based cis-Regulatory Gene
Networks

• Hamid Bolouri and Eric H. Davidson
• Presented by Geoffrey

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Introduction

• Cis-Regulatory elements can be regarded as pieces
  of DNA sequences that have target site sequences
  recognized by binding proteins
• They are genetically hardwired information
  processors and are linked together to form a huge
  network
• Each element receives informational input that
  determines its activity and produces an
  informational output in the form of regulatory
  instructions (i.e. activates or inhibits other
  elements)

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Introduction

• Genetic regulatory apparatus remains unchanged in
  every cell. What it does will depend on the
  inputs that it receives at each point in time
• Part of the inputs depends on prior transactions
  of genes that synthesize the necessary factors,
  and part on other events, such as extra-cellular
  signals

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Cis-Regulatory Elements

• Each element carries out some processing of its
  input information
• Inputs are often multiple while the output is a
  unique function that informs the basal
  transcription apparatus how frequently to
  initiate transcription
• Example of an element in diagram form

• (This diagram shows a gene whose expression is
  activated by Ubiquitous activator and inhibited
  by protein A)

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Cis-Regulatory Elements in Development

• Cis-Regulatory information processing is
  important in development because development
  depends fundamentally on spatial (which type of
  cells and where) and temporal (when) control of
  gene expression
• These decisions result from logic functions
  carried out by the regulatory elements
• For example, a given cis-regulatory element might
  lead to the expression of a gene when two inputs
  overlap (AND operation), resulting in the
  appearance of a new factor or it might control
  the expression through the interplay between
  positive and negative inputs.

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Cis-Regulatory Elements in Development

• Hence thinking about cis-regulatory elements from
  an informational point of view leads to the
  mutable, measurable and regulatory properties of
  genomic DNA
• The gene sequence of each element will dictate
  which input the element will listen to and the
  functions it is capable of processing
• Each input hence indicates a target site sequence
  that can be tested and recognized via mutation or
  gene transfer

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Illustration Endo16 Model

• The cis-regulatory system of the endo16 gene of
  the sea urchin has been studied in great detail
• It has a modestly complex pattern of expression
  during its embryogenesis
• It is activated in the vegetal plate of the
  embryo, specifically in the Veg2 lineage, at
  about the 8th cleavage
• The Veg2 lineage consists of the progeny of eight
  6th cleavage founder cells, and from it derives
  most of the endoderms

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Illustration Endo16 Model

• The endo16 gene is transcribed in this
  endomesodermal field until gastrulation (process
  by which germ cells of the blastoderm are
  translocated to new positions in the embryo),
  during which it is expressed throughout the
  invaginating archenteron but no longer in the
  mesodermal domain

• As the gut become regionalized, expression is
  extinguished in the foregut and hindgut but
  accelerated in the midgut where it continues to
  be expressed in the feeding larva

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Illustration Endo16 Model

• Summary of the expression pattern of endo16 gene
  (shown in blue)

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Illustration Endo16 Model

• The cis-regulatory system that controls the
  endo16 expression is about 2300 base pairs in
  length and it consists of several clusters of
  target sites that execute distinct functions,
  hence each can be thought of as separable modular
  regulatory elements

• The basal transcription apparatus (Bp) has no
  regulatory activity on its own and is used to
  service regulatory elements expressed in every
  domain of the embryo

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Illustration Endo16 Model

• Modules A and B carry out many interesting
  regulatory functions
• They have altogether 17 target sites for factors
  that recognize and bind specifically at given
  sequences

• A protein, SpGCF1, interacts at 5 sites of module
  A. The other 12 target sites are serviced by 9
  different transcription factors where each
  interaction has a distinct and measurable
  functional meaning
• The details of the interaction are shown in the
  box below. The target sites are indicated by
  boxes (blue for Module B and red for Module A).
  The arrows lead from the target site to the logic
  operations indicated in circles. The logic
  operation will then state how the factors will
  interact

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Illustration Endo16 Model

• The complete model of the endo16 expression is
  shown in the figure below. The elements now are
  the individual genes that are involved in the
  expression
• Details of the model can be seen here click

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Logic Operation

• The model specifies logic operations by which the
  inputs are processed and the altered values are
  carried forward
• Common operations includes
• AND when all the conditions are met, then the
  indicated operations on the value of the output
  at that node will take place
• OR when one (or some) of the conditions are
  met, then the indicated operations will take
  place

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Logic Operation

• There are direct physical implications of the
  logic operations. The AND operator shows that
  the proteins binding at the respective sites are
  together necessary for the function to occur
  (e.g. formation of a huge functional complex by
  the transcriptional factors)
• However, it does not necessary mean that it is an
  all-or-none output. Alternate outputs with values
  could be associated with inputs not being present
  by adding the else portion
• The point is that the model describes the
  functions that are mediated by each site,
  conditional on the inputs present. It does not
  attempt to describe the biochemistry of the
  proteins that contribute to this function
• Simply put, they are just information processing
  constructs similar to those that can be found in
  normal programming languages

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Continuous and Boolean Functions

• Taking again the computational model as an
  example

• The fill in boxes with solid lines extending
  indicates inputs where the amplitude varies over
  time, e.g. UI, R, OTX
• Open boxes with dashed lines indicate inputs that
  are often present in excess, and hence can be
  regarded as boolean inputs, i.e. either they are
  present, or they are not
• Open boxes with thin lines indicate scalar
  operations on the inputs of the node

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Continuous and Boolean Functions

• Hence the endo16 model is not a kinetic model per
  se
• It does not consist of a set of time based
  differential equations describing the kinetic
  reactions
• Instead, it describes the logic functions
  mediated by the DNA target sites
• Although it is not something new in other fields,
  say, engineering, but it does offer a refreshing
  way of modeling gene regulatory networks, which
  are predominantly based on differential equations

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Models for Networks of cis-Regulatory Elements
Symbolism and Significance

• All major processes in animal development are
  driven forward by regulatory genes, i.e. genes
  that express transcription factors
• Development events are not discrete and the
  regulatory networks that control development are
  often connected to other networks that control
  prior and surrounding processes in both the
  spatial and temporal domains
• The model used for the cis-Regulatory elements
  can be used to model the beginning of the process
  for which the network displays the genetic
  program, as well as the end, which is the
  activation of gene batteries (a series of genes),
  e.g. endo16 which expresses an adhesion protein
  involved in the gastrulation of the sea urchin
  embryo

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General Purposes of DNA sequence based Network
Models

• The objective of such a model is to
• State the key inputs and outputs of the
  cis-regulatory system
• Explain why each gene runs where and when it does
• How the spatial territories are being built up
• Even incomplete models are informative as the
  interactions found always have some functional
  meaning
• Each cis-regulatory system can also be considered
  as a black box which can be connected to other
  systems

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Genomic and Nuclear Views

• A useful concept for DNA sequence-level network
  is the distinction between View from Genome and
  View from Nucleus
• The VFG shows all the interactions that the
  system is capable of while the VFN focus on those
  sites that are occupied by the indicated inputs
  in any given nucleus at any given time, i.e.
  snapshot

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Genomic and Nuclear Views

• A simple illustration is shown in the figure.
  Here there are two spatial domains of an embryo
  domain A, and the rest (A)
• The VFG shows that there is a ubiquitous positive
  activator needed for all three genes. But gene 1
  also requires another positive input to be
  activated and it acts positively in domain A and
  negatively in others (A)
• This will then affect the expression of gene 2
  and gene 3
• Hence in any development stage, either VFN(A) or
  VFN(A) could be possible

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Conclusion

• Cis-Regulatory networks serve as a development
  biologists essential organizer for getting
  causal relationship between genes
• They are essential due to the myriad of
  information and possible interactions that may
  occur
• The models used are not actually genetic models
  although their key elements are genomic target
  site sequence elements
• The relationship between the elements can be
  viewed from several angles, i.e. views VFG,
  VFN, Black Box View (Birds eye view). No
  transformations are needed to transit from one
  view to another
• The model serves also as a predictive tool,
  enabling developmental biologists to see what
  might happen to the regulatory system if a target
  site is mutated or experimentally altered