“controls” for genome-wide analysis

Dear all,

'd like to have you suggestions please about the adequate "controls" when performing genome-wide analysis. For example, let's consider 1000 UP_REGULATED genes with increased PROTEIN X and HISTONE MARK Y (on the gene promoters or enhancers):

in order to show that PROTEIN X is related to HISTONE MARK Y for 1000 UP-regulated genes, what "controls" would you use for comparison :

-- 1000 RANDOM GENES

-- 1000 UP-REG GENES with NO PROTEIN X, NO HISTONE MARK Y

-- 1000 UP-REG GENES with PROTEIN X, and NO HISTONE MARK Y

-- 1000 UP-REG GENES with NO PROTEIN X, and with HISTONE MARK Y

-- 1000 NOT-UP-REG GENES with NO PROTEIN X, NO HISTONE MARK Y

-- 1000 NOT-UP-REG GENES with PROTEIN X, and NO HISTONE MARK Y

-- 1000 NOT-UP-REG GENES with NO PROTEIN X, and with HISTONE MARK Y

-- anything else ?

thanks a lot,

-- bogdan