The activity of hundreds of genes was altered when people's sleep was cut to less than six hours a day for a week.
Writing in the journal PNAS, the researchers said the results helped explain how poor sleep damaged health.
Heart disease, diabetes, obesity and poor brain function have all been linked to substandard sleep.
What missing hours in bed actually does to alter health, however, is unknown.
So researchers at the University of Surrey analysed the blood of 26 people after they had had plenty of sleep, up to 10 hours each night for a week, and compared the results with samples after a week of fewer than six hours a night.
More than 700 genes were altered by the shift. Each contains the instructions for building a protein, so those that became more active produced more proteins - changing the chemistry of the body.
Meanwhile the natural body clock was disturbed - some genes naturally wax and wane in activity through the day, but this effect was dulled by sleep deprivation.
Prof Colin Smith, from the University of Surrey, told the BBC: There was quite a dramatic change in activity in many different kinds of genes.
Areas such as the immune system and how the body responds to damage and stress were affected.
