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Chapter 5 : Rewiring Transcriptional Circuitry: Mating-Type Regulation in and as a Model for Evolution

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Abstract:

This chapter discusses insights into transcriptional evolution that have arisen from detailed comparisons of the mating circuitry in and the related ascomycete . The chapter reviews major concepts in mating-type regulation in which have been established over the past several decades. It then reviews more recent work describing mating-type determination in , a pathogenic yeast that last shared a common ancestor with some 200 to 800 million years ago. Close comparison of the two circuits reveals multiple changes in transcriptional regulation, which fall into distinct mechanistic classes, and also provides multiple examples of both phenotypic variance and phenotypic conservation accompanying transcriptional regulatory evolution. a, α, and a/α cells each follow distinct transcriptional regulatory programs. a and α cells are specialized for mating with each other: a cells express the a-specific genes (asgs), which include a mating pheromone for communicating with α cells (a-factor) and a pheromone receptor which detects pheromone signals from α cells . and share several important overall similarities in their mating-type regulatory circuits. First, a cells can mate with α cells, forming nonmating a/α cells. Second, mating type is determined by orthologous site-specific DNA binding proteins encoded at the MAT locus. Mating-type regulation in has long served as a model system to understand principles of gene regulation, cell-to-cell signaling, polarized growth, cell fusion, and many other aspects of cell and molecular biology.

Citation: Tsong A, Tuch B, Johnson A. 2007. Rewiring Transcriptional Circuitry: Mating-Type Regulation in and as a Model for Evolution, p 75-89. In Heitman J, Kronstad J, Taylor J, Casselton L (ed), Sex in Fungi. ASM Press, Washington, DC. doi: 10.1128/9781555815837.ch5
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Image of Figure 5.1
Figure 5.1

Mechanisms underlying the evolution of transcriptional regulation. In principle, transcriptional regulatory circuits may change through a variety of mechanisms. For instance, an individual gene can come under the control of an existing transcriptional regulatory circuit through changes in the elements within its promoter (a); a factor may evolve such that its binding specificity has changed (b); or a factor may evolve such that its activity has changed—for instance, by gaining an interaction with another protein (c).

Citation: Tsong A, Tuch B, Johnson A. 2007. Rewiring Transcriptional Circuitry: Mating-Type Regulation in and as a Model for Evolution, p 75-89. In Heitman J, Kronstad J, Taylor J, Casselton L (ed), Sex in Fungi. ASM Press, Washington, DC. doi: 10.1128/9781555815837.ch5
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Image of Figure 5.2
Figure 5.2

has three distinguishable mating types. (a) forms three mating types: , α, and /α. and α cells can mate with each other to form an /α cell. /α cells cannot mate, but they can undergo meiosis, regenerating and α cells. (b) Mating type is determined by a short segment of DNA called the , or mating type locus. Cells that express only or α are or α cells, respectively, while cells that express both alleles are /α. The loci encode sequence-specific DNA binding proteins. a1 and α2 are homeodomain proteins, and α1 is an α-domain protein.

Citation: Tsong A, Tuch B, Johnson A. 2007. Rewiring Transcriptional Circuitry: Mating-Type Regulation in and as a Model for Evolution, p 75-89. In Heitman J, Kronstad J, Taylor J, Casselton L (ed), Sex in Fungi. ASM Press, Washington, DC. doi: 10.1128/9781555815837.ch5
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Figure 5.3

The three cell types of follow unique transcriptional programs. (a) ,α, and /α cells each follow distinct transcriptional regulatory programs, directed by the sequence-specific DNA binding proteins encoded by and α. These proteins control mating type by regulating three groups of genes: the -specific genes (sgs), the α-specific genes (αsgs), and the haploid-specific genes (hsgs). The unique combination of site-specific DNA binding proteins in each cell type results in differential expression of the sgs, αsgs, and hsgs. (b) Different elements (“operators”), bound by the -encoded DNA binding proteins, are required for the regulation of the sgs, αsgs, and hsgs.

Citation: Tsong A, Tuch B, Johnson A. 2007. Rewiring Transcriptional Circuitry: Mating-Type Regulation in and as a Model for Evolution, p 75-89. In Heitman J, Kronstad J, Taylor J, Casselton L (ed), Sex in Fungi. ASM Press, Washington, DC. doi: 10.1128/9781555815837.ch5
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Image of Figure 5.4
Figure 5.4

carries silent copies of both and α. Individual haploid cells express only or α, but they carry transcriptionally silenced copies of both loci, called and . Information from either or can be copied into the expressed locus in a highly regulated process of gene conversion, resulting in the switching of mating types.

Citation: Tsong A, Tuch B, Johnson A. 2007. Rewiring Transcriptional Circuitry: Mating-Type Regulation in and as a Model for Evolution, p 75-89. In Heitman J, Kronstad J, Taylor J, Casselton L (ed), Sex in Fungi. ASM Press, Washington, DC. doi: 10.1128/9781555815837.ch5
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Figure 5.5

The locus. The locus encodes 10 genes, 4 of which are sequence-specific DNA binding proteins (see key). a1, α1, and α2 have orthologs in the locus and are conserved in their direction of transcription, location of introns, and overall configuration within the locus. The locus also encodes several additional genes. These include the HMG domain protein a2, as well as and α alleles of an oxysterol binding protein (), a phosphatidyl inositol kinase (), and a poly(A) polymerase ().

Citation: Tsong A, Tuch B, Johnson A. 2007. Rewiring Transcriptional Circuitry: Mating-Type Regulation in and as a Model for Evolution, p 75-89. In Heitman J, Kronstad J, Taylor J, Casselton L (ed), Sex in Fungi. ASM Press, Washington, DC. doi: 10.1128/9781555815837.ch5
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Figure 5.6

White-opaque switching in is under locus control. (Top) White colony with an opaque sector. (Middle) Scanning electron micrographs of white and opaque cells. White cells are rounder, while opaque cells are elongated and show distinct cell membrane properties. (Bottom) The switch from white to opaque is blocked by the a1-α2 protein complex; as a result, cells expressing both and α cannot switch. Images courtesy of Mathew Miller, University of California, San Francisco.

Citation: Tsong A, Tuch B, Johnson A. 2007. Rewiring Transcriptional Circuitry: Mating-Type Regulation in and as a Model for Evolution, p 75-89. In Heitman J, Kronstad J, Taylor J, Casselton L (ed), Sex in Fungi. ASM Press, Washington, DC. doi: 10.1128/9781555815837.ch5
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Figure 5.7

The white-opaque transition is required for mating in . In order to mate, and α cells must first switch to the mating-competent opaque state.

Citation: Tsong A, Tuch B, Johnson A. 2007. Rewiring Transcriptional Circuitry: Mating-Type Regulation in and as a Model for Evolution, p 75-89. In Heitman J, Kronstad J, Taylor J, Casselton L (ed), Sex in Fungi. ASM Press, Washington, DC. doi: 10.1128/9781555815837.ch5
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Figure 5.8

Comparison of the and mating-type genetic circuits. In , a2 from the locus activates -type mating, while α1 from the α locus activates α-type mating. In an /α cells, which carry both and α, a1 and α2 work together to repress the white-opaque switch, which precedes mating. This circuit differs from that of , where -type mating requires no input from the locus and is instead repressed by α2 in α and a/α cells.

Citation: Tsong A, Tuch B, Johnson A. 2007. Rewiring Transcriptional Circuitry: Mating-Type Regulation in and as a Model for Evolution, p 75-89. In Heitman J, Kronstad J, Taylor J, Casselton L (ed), Sex in Fungi. ASM Press, Washington, DC. doi: 10.1128/9781555815837.ch5
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Image of Figure 5.9
Figure 5.9

Comparison of the and mating-type transcriptional circuits. In white-phase cells, a1-α2 represses nine genes directly, several of which are orthologous to hsgs of (orthologous genes regulated by orthologous proteins are marked with a gray line). a1-α2 also represses the switch from the white phase to the mating-competent opaque phase. If either component of a1-α2 is absent (for instance, in or α cells), the cell may switch to the opaque state under appropriate environmental conditions. This switch is accompanied by the up- or downregulation of nearly 450 genes. αsgs are activated by α1, but only if the cells are in the opaque phase. sgs are activated by a2, but only if the cells are in the opaque phase and have been exposed to α pheromone. Note two major differences between the and mating circuits. First, in contrast to , relief of a1-α2 repression is necessary but not sufficient for mating competence in , as must further undergo the white-opaque transition prior to mating. Second, a2 is required for activation of the sgs in . In , sgs are on by default and are repressed in α and /α cells by α2. Hence, α2 has two roles in : to repress the hsgs with a1, and to repress the sgs. Despite these changes, the overall output of the circuit is identical in and : cells mate with α cells to form nonmating /α cells.

Citation: Tsong A, Tuch B, Johnson A. 2007. Rewiring Transcriptional Circuitry: Mating-Type Regulation in and as a Model for Evolution, p 75-89. In Heitman J, Kronstad J, Taylor J, Casselton L (ed), Sex in Fungi. ASM Press, Washington, DC. doi: 10.1128/9781555815837.ch5
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Image of Figure 5.10
Figure 5.10

sg activation in requires the sg operator, which comprises an a2 binding site and an Mcm1 binding site. The sg operator is shown for comparison. The a2 recognition site and the α2 recognition site differ by a single base pair deletion; note also that the AT content flanking the Mcm1 site is higher in than in .

Citation: Tsong A, Tuch B, Johnson A. 2007. Rewiring Transcriptional Circuitry: Mating-Type Regulation in and as a Model for Evolution, p 75-89. In Heitman J, Kronstad J, Taylor J, Casselton L (ed), Sex in Fungi. ASM Press, Washington, DC. doi: 10.1128/9781555815837.ch5
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Image of Figure 5.11
Figure 5.11

controls the white-opaque switch. a1-α2 represses a master regulator of white-opaque switching, . In and α cells, which lack a1-α2, is expressed at low levels. On occasion, the concentration of Wor1 protein surpasses a threshold and activates transcription from its own promoter, resulting in a positive-feedback loop and differentiation into the opaque state.

Citation: Tsong A, Tuch B, Johnson A. 2007. Rewiring Transcriptional Circuitry: Mating-Type Regulation in and as a Model for Evolution, p 75-89. In Heitman J, Kronstad J, Taylor J, Casselton L (ed), Sex in Fungi. ASM Press, Washington, DC. doi: 10.1128/9781555815837.ch5
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Image of Figure 5.12
Figure 5.12

loci from various ascomycetes are mapped onto a phylogenetic tree. An HMG box ortholog of a2 is present in the loci of extant species spanning up to 1 billion years of evolution; moreover, this ortholog is required for -type mating in many species, including , , , , , , and . The lineage carrying lost this regulator after its divergence from

Citation: Tsong A, Tuch B, Johnson A. 2007. Rewiring Transcriptional Circuitry: Mating-Type Regulation in and as a Model for Evolution, p 75-89. In Heitman J, Kronstad J, Taylor J, Casselton L (ed), Sex in Fungi. ASM Press, Washington, DC. doi: 10.1128/9781555815837.ch5
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Image of Figure 5.13
Figure 5.13

The sgs were positively regulated by a2 in the common ancestor of and but are negatively regulated by α2 in Yeasts in the lineage, including , , , and , show hallmarks of both positive and negative regulation of the sgs, as evaluated by bioinformatic analysis of both sg operators and α2 and Mcm1 protein sequence. Given the phylogenetic relationships of , , and , this suggests that α2-mediated repression of the sgs evolved prior to the loss of a2.

Citation: Tsong A, Tuch B, Johnson A. 2007. Rewiring Transcriptional Circuitry: Mating-Type Regulation in and as a Model for Evolution, p 75-89. In Heitman J, Kronstad J, Taylor J, Casselton L (ed), Sex in Fungi. ASM Press, Washington, DC. doi: 10.1128/9781555815837.ch5
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